Gene: SETD5 -
Human Gene Module
/ Chromosome 3 /
SETD5
SETD5
SET domain containing 5
SFARI Gene Score
1S
High Confidence, Syndromic
Criteria 1.1, Syndromic
Autism Reports /
Total Reports
22
/ 52
Rare Variants /
Common Variants
177
/ 0
EAGLE Score
28.05
Strong
Aliases
Associated Syndromes
KBG syndrome
Chromosome Band
3p25.3
Associated Disorders
DD/NDD, ADHD, ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%). Two de novo protein-truncating variants in SETD5 were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; additional protein-truncating variants in this gene were observed in case samples from the Danish iPSYCH study in this report. Furthermore, TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified SETD5 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SETD5 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
This gene is predicted to encode a methyltransferase and resides within the critical interval for the 3p25 microdeletion syndrome.
External Links
Gene Card
Open Targets Platform
gnomAD browser
PubMed
Human
Entrez Gene
UniProt
HumanBase
VariCarta
Mouse
Entrez Gene
Mouse Genome Informatics
Allen Brain Atlas
SFARI Genomic Platforms
GPF browser
SFARI genome browser
Reports (52)
Variants (177)
Gene Score
Protein Interactions (5)
Reports related to SETD5
(52 Reports)
Type
Title
Author, Year
Autism Report
Associated Disorders
Support
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Neale BM , et al. (2012)
Yes
Support
De novo gene disruptions in children on the autistic spectrum
Iossifov I , et al. (2012)
Yes
Support
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study
Rauch A , et al. (2012)
No
Support
Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region
Kellogg G , et al. (2013)
No
Primary
De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability
Grozeva D , et al. (2014)
No
OCD, ASD
Support
Convergence of genes and cellular pathways dysregulated in autism spectrum disorders
Pinto D , et al. (2014)
Yes
Support
Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome
Kuechler A , et al. (2014)
No
Recent Recommendation
Synaptic, transcriptional and chromatin genes disrupted in autism
De Rubeis S , et al. (2014)
Yes
Support
Large-scale discovery of novel genetic causes of developmental disorders
Deciphering Developmental Disorders Study (2014)
No
10
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission
Iossifov I , et al. (2015)
Yes
11
Support
Mutations in HECW2 are associated with intellectual disability and epilepsy
Halvardson J , et al. (2016)
No
12
Support
SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression
Szczauba K , et al. (2016)
No
13
Support
Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases
Farwell Hagman KD , et al. (2016)
No
14
Support
De novo genic mutations among a Chinese autism spectrum disorder cohort
Wang T , et al. (2016)
Yes
15
Support
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases
Stessman HA , et al. (2017)
No
16
Support
SETD5 gene variant associated with mild intellectual disability - a case report
Stur E , et al. (2017)
No
17
Recent Recommendation
Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance
Powis Z , et al. (2017)
No
ADHD, ASD
18
Support
Expanding the genetic heterogeneity of intellectual disability
Anazi S , et al. (2017)
No
ADHD
19
Support
Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
Zhao JJ , et al. (2017)
No
Dysmorphic features, MCA
20
Support
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands
Jin SC , et al. (2017)
No
Neurodevelopmental disorders (NDD)
21
Support
Exome Pool-Seq in neurodevelopmental disorders
Popp B , et al. (2017)
No
Hypotonia
22
Recent Recommendation
Genetic variations on SETD5 underlying autistic conditions
Fernandes IR , et al. (2018)
No
Autistic features
23
Recent Recommendation
Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition
Deliu E , et al. (2018)
No
24
Support
A novel mutation in a common pathogenic gene ( SETD5) associated with intellectual disability: A case report
Fang YL , et al. (2019)
No
DD, ID
25
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
Satterstrom FK et al. (2020)
Yes
26
Support
SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome
Crippa M et al. (2020)
No
ASD
27
Support
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Wang T et al. (2020)
Yes
28
Support
Brunet T et al. (2021)
No
29
Support
Mahjani B et al. (2021)
Yes
30
Support
Hu C et al. (2022)
Yes
31
Support
Zhou X et al. (2022)
Yes
32
Support
Gabellini C et al. (2022)
Yes
33
Support
Spataro N et al. (2023)
No
ADHD, autistic features
34
Support
Zaghi M et al. (2023)
No
35
Support
Sanchis-Juan A et al. (2023)
No
36
Support
Sheth F et al. (2023)
Yes
DD, ID
37
Support
Karthika Ajit Valaparambil et al. ()
Yes
38
Support
Erica Rosina et al. (2024)
No
39
Support
M Cecilia Poli et al. ()
No
40
Support
Tamam Khalaf et al. (2024)
No
41
Support
Ruohao Wu et al. (2024)
Yes
42
Support
Laura E Burnett et al. ()
Yes
43
Support
Axel Schmidt et al. (2024)
No
44
Support
Hosneara Akter et al. ()
Yes
ADHD, epilepsy/seizures
45
Support
Alessandro De Falco et al. ()
No
ADHD, epilepsy/seizures, autistic features, stereo
46
Support
Steven Laurie et al. (2025)
Yes
47
Support
Nora C Callahan et al. ()
No
ASD, ADHD, ID
48
Support
Shoko Sashiyama et al. (2025)
No
Autosomal dominant intellectual developmental diso
49
Support
Zhiwei Wang et al. (2025)
Yes
50
Support
Vittoria Greco et al. (2025)
Yes
ID
51
Support
Suzanne M Musgrave et al. (2024)
Yes
52
Support
Alekh Paranjapye et al. (2025)
Yes
Rare Variants
(177)
Status
Allele Change
Residue Change
Variant Type
Inheritance Pattern
Parental Transmission
Family Type
PubMed ID
Author, Year
copy_number_loss
De novo
25138099
Kuechler A , et al. (2014)
copy_number_loss
Unknown
38438125
Tamam Khalaf et al. (2024)
c.*3dup
frameshift_variant
De novo
33004838
Wang T et al. (2020)
copy_number_loss
De novo
Unknown
24768552
Pinto D , et al. (2014)
copy_number_loss
De novo
Simplex
32793091
Crippa M et al. (2020)
copy_number_loss
De novo
39603091
Alessandro De Falco et al. ()
c.195T>A
p.Ser65%3D
stop_gained
Unknown
33004838
Wang T et al. (2020)
c.1782+1G>T
splice_site_variant
Unknown
33004838
Wang T et al. (2020)
c.1576G>T
p.Glu526Ter
stop_gained
Unknown
33004838
Wang T et al. (2020)
c.2021T>G
p.Leu674Ter
stop_gained
Unknown
33004838
Wang T et al. (2020)
c.2205C>G
p.Thr735%3D
stop_gained
Unknown
33004838
Wang T et al. (2020)
c.2644C>T
p.Arg882Ter
stop_gained
De novo
33004838
Wang T et al. (2020)
c.2644C>T
p.Arg882Ter
stop_gained
Unknown
33004838
Wang T et al. (2020)
c.71+876dup
frameshift_variant
De novo
28881385
Powis Z , et al. (2017)
c.3520C>T
p.Arg1174Ter
stop_gained
Unknown
33004838
Wang T et al. (2020)
c.1333C>T
p.Arg445Ter
stop_gained
De novo
28991257
Jin SC , et al. (2017)
c.71+2260del
frameshift_variant
De novo
28881385
Powis Z , et al. (2017)
c.1783-2A>T
splice_site_variant
De novo
28881385
Powis Z , et al. (2017)
c.2347-7A>G
splice_site_variant
De novo
28881385
Powis Z , et al. (2017)
c.2476+1G>A
splice_site_variant
Simplex
28940097
Anazi S , et al. (2017)
c.598G>T
p.Glu200Ter
stop_gained
Unknown
34615535
Mahjani B et al. (2021)
c.814C>T
p.Gln272Ter
stop_gained
Unknown
34615535
Mahjani B et al. (2021)
c.3001C>T
p.Arg1001Ter
stop_gained
De novo
28881385
Powis Z , et al. (2017)
c.651T>G
p.Tyr217Ter
stop_gained
De novo
40265665
Nora C Callahan et al. ()
c.625C>T
p.Arg209Trp
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.554C>T
p.Thr185Met
missense_variant
De novo
35982159
Zhou X et al. (2022)
c.977T>C
p.Leu326Pro
missense_variant
De novo
35982159
Zhou X et al. (2022)
c.2347-7A>G
splice_region_variant
De novo
36980980
Spataro N et al. (2023)
c.1333C>T
p.Arg445Ter
stop_gained
De novo
40265665
Nora C Callahan et al. ()
c.1474G>T
p.Glu492Ter
stop_gained
De Novo
40265665
Nora C Callahan et al. ()
c.2644C>T
p.Arg882Ter
stop_gained
De novo
40265665
Nora C Callahan et al. ()
c.1030G>A
p.Gly344Ser
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.1591C>T
p.Arg531Trp
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.1663G>A
p.Gly555Ser
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.1763G>A
p.Arg588Gln
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.2237C>T
p.Pro746Leu
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.2269C>T
p.Arg757Cys
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.2300G>A
p.Arg767His
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.2348G>A
p.Arg783His
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.2416C>T
p.Gln806Ter
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.2698C>T
p.Arg900Cys
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.2932C>T
p.Arg978Trp
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.2933G>A
p.Arg978Gln
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.2509C>T
p.Arg837Cys
missense_variant
De novo
35982159
Zhou X et al. (2022)
c.3001C>T
p.Arg1001Ter
stop_gained
De novo
40265665
Nora C Callahan et al. ()
c.1783-2A>G
splice_site_variant
De novo
39039281
Axel Schmidt et al. (2024)
c.3407C>T
p.Ser1136Phe
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.3731G>A
p.Cys1244Tyr
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.3929C>T
p.Ser1310Leu
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.3235A>G
p.Lys1079Glu
missense_variant
De novo
35982159
Zhou X et al. (2022)
c.4216T>A
p.Ser1406Thr
missense_variant
De novo
35982159
Zhou X et al. (2022)
c.59G>A
p.Gly20Glu
missense_variant
Unknown
39342494
Hosneara Akter et al. ()
c.2983C>T
p.Arg995Ter
stop_gained
Unknown
38438125
Tamam Khalaf et al. (2024)
c.2302C>T
p.Arg768Ter
stop_gained
De novo
39039281
Axel Schmidt et al. (2024)
c.1967del
p.Leu656Ter
frameshift_variant
De novo
33004838
Wang T et al. (2020)
c.182G>A
p.Arg61Gln
missense_variant
Unknown
39342494
Hosneara Akter et al. ()
c.3556C>T
p.Arg1186Ter
stop_gained
De novo
39039281
Axel Schmidt et al. (2024)
c.477A>T
p.Glu159Asp
missense_variant
Unknown
39342494
Hosneara Akter et al. ()
c.485T>A
p.Leu162Ter
stop_gained
De novo
39603091
Alessandro De Falco et al. ()
c.2734C>T
p.Arg912Ter
stop_gained
Familial
Maternal
33004838
Wang T et al. (2020)
c.1524+1G>A
splice_site_variant
Familial
Paternal
27824329
Wang T , et al. (2016)
c.2302C>T
p.Arg768Ter
stop_gained
De novo
Simplex
23020937
Rauch A , et al. (2012)
c.2302C>T
p.Arg768Ter
stop_gained
De novo
Simplex
28990276
Zhao JJ , et al. (2017)
c.2561C>T
p.Pro854Leu
missense_variant
Unknown
39342494
Hosneara Akter et al. ()
c.2683A>G
p.Met895Val
missense_variant
Unknown
39342494
Hosneara Akter et al. ()
c.71+904A>G
intron_variant
De novo
Simplex
31981491
Satterstrom FK et al. (2020)
c.1194T>G
p.Tyr398Ter
stop_gained
De novo
39603091
Alessandro De Falco et al. ()
c.71+1947_71+1948insA
frameshift_variant
De novo
28881385
Powis Z , et al. (2017)
c.3338A>G
p.His1113Arg
missense_variant
Unknown
40642607
Zhiwei Wang et al. (2025)
c.4181C>G
p.Ala1394Gly
missense_variant
Unknown
40642607
Zhiwei Wang et al. (2025)
c.3526C>T
p.Arg1176Ter
stop_gained
De novo
39603091
Alessandro De Falco et al. ()
c.894A>G
p.Ile298Met
missense_variant
De novo
Simplex
35982159
Zhou X et al. (2022)
c.1195A>T
p.Lys399Ter
stop_gained
De novo
Simplex
24680889
Grozeva D , et al. (2014)
c.1043G>A
p.Arg348Gln
missense_variant
De novo
28191889
Stessman HA , et al. (2017)
c.2929T>A
p.Phe977Ile
missense_variant
Familial
Paternal
35741772
Hu C et al. (2022)
c.3001C>T
p.Arg1001Ter
stop_gained
De novo
Simplex
24680889
Grozeva D , et al. (2014)
c.922C>T
p.Arg308Ter
stop_gained
De novo
Simplex
25363760
De Rubeis S , et al. (2014)
c.598G>T
p.Glu200Ter
stop_gained
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.922C>T
p.Arg308Ter
stop_gained
De novo
Simplex
38041506
Erica Rosina et al. (2024)
c.960-5C>G
p.?
splice_region_variant
De novo
39603091
Alessandro De Falco et al. ()
c.848G>A
p.Arg283Gln
missense_variant
Familial
Maternal
33004838
Wang T et al. (2020)
c.2949del
p.Met984CysfsTer7
frameshift_variant
Unknown
33004838
Wang T et al. (2020)
c.4032_4033del
p.Ala1345Ter
frameshift_variant
Unknown
33004838
Wang T et al. (2020)
c.2347-7A>G
p.?
splice_region_variant
De novo
39603091
Alessandro De Falco et al. ()
c.1022G>A
p.Arg341His
missense_variant
Familial
Paternal
33004838
Wang T et al. (2020)
c.1125dup
p.Val376CysfsTer9
frameshift_variant
De novo
29158550
Popp B , et al. (2017)
c.3737G>T
p.Ser1246Ile
missense_variant
Unknown
Simplex
37543562
Sheth F et al. (2023)
c.2158G>T
p.Glu720Ter
stop_gained
De novo
Simplex
27334371
Halvardson J , et al. (2016)
c.814C>T
p.Gln272Ter
stop_gained
De novo
Simplex
31981491
Satterstrom FK et al. (2020)
c.2476+2T>C
splice_site_variant
Unknown
Simplex
37541188
Sanchis-Juan A et al. (2023)
c.1135A>T
p.Ile379Phe
missense_variant
De novo
39603091
Alessandro De Falco et al. ()
c.1965T>G
p.Ser655Arg
missense_variant
De novo
39603091
Alessandro De Falco et al. ()
c.2093A>G
p.Lys698Arg
missense_variant
De novo
39603091
Alessandro De Falco et al. ()
c.2179A>G
p.Thr727Ala
missense_variant
De novo
39603091
Alessandro De Falco et al. ()
c.3929C>T
p.Ser1310Leu
missense_variant
Familial
Maternal
33004838
Wang T et al. (2020)
c.4106dup
p.Ser1370GlufsTer10
frameshift_variant
Unknown
33004838
Wang T et al. (2020)
c.1405G>A
p.Val469Ile
missense_variant
De novo
Simplex
22495311
Neale BM , et al. (2012)
c.547_567+60del
splice_site_variant
De novo
Simplex
25138099
Kuechler A , et al. (2014)
c.2438dup
p.Asn814GlufsTer2
frameshift_variant
De novo
36980980
Spataro N et al. (2023)
c.3196-2A>G
splice_site_variant
Familial
Both parents
38177409
M Cecilia Poli et al. ()
c.1350G>C
p.Glu450Asp
missense_variant
Unknown
40756852
Suzanne M Musgrave et al. (2024)
p.Thr552AsnfsTer5
frameshift_variant
De novo
27513193
Farwell Hagman KD , et al. (2016)
c.3246del
p.Ala1083LeufsTer61
frameshift_variant
De novo
28881385
Powis Z , et al. (2017)
c.2788dup
p.Cys930LeufsTer3
frameshift_variant
De novo
40265665
Nora C Callahan et al. ()
c.2005G>A
p.Gly669Arg
missense_variant
De novo
Simplex
22542183
Iossifov I , et al. (2012)
c.367C>T
p.Arg123Trp
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.952T>C
p.Phe318Leu
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.966C>A
p.Tyr322Ter
stop_gained
Familial
Paternal
39603091
Alessandro De Falco et al. ()
c.1013_1014del
p.Val338GlyfsTer7
frameshift_variant
Unknown
33004838
Wang T et al. (2020)
c.2305del
p.Arg769GlyfsTer17
frameshift_variant
De Novo
40265665
Nora C Callahan et al. ()
c.1405G>A
p.Val469Ile
missense_variant
De novo
Simplex
25363760
De Rubeis S , et al. (2014)
c.1022G>A
p.Arg341His
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.2164C>G
p.Pro722Ala
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.2307G>T
p.Arg769Ser
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.2348G>A
p.Arg783His
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.2351G>A
p.Trp784Ter
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.2920G>C
p.Asp974His
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.2942T>G
p.Phe981Cys
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.1081C>T
p.Arg361Ter
stop_gained
Familial
Maternal
39603091
Alessandro De Falco et al. ()
c.2734C>T
p.Arg912Ter
stop_gained
Familial
Maternal
39603091
Alessandro De Falco et al. ()
c.3066_3087dup
p.Glu1030ArgfsTer8
frameshift_variant
Unknown
33004838
Wang T et al. (2020)
c.1401dupA
p.Glu468ArgfsTer11
frameshift_variant
Unknown
40265665
Nora C Callahan et al. ()
c.3773G>C
p.Ser1258Thr
missense_variant
De novo
Simplex
25363760
De Rubeis S , et al. (2014)
c.3305G>A
p.Gly1102Asp
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.3527G>A
p.Arg1176Gln
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.3635C>T
p.Pro1212Leu
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.3907G>A
p.Ala1303Thr
missense_variant
Unknown
Unknown
25363760
De Rubeis S , et al. (2014)
c.2352G>T
p.Trp784Cys
missense_variant
Unknown
Simplex
39825153
Steven Laurie et al. (2025)
c.71+1186_71+1201del
frameshift_variant
Unknown
Not simplex
28940097
Anazi S , et al. (2017)
c.1782+1G>T
p.?
splice_site_variant
Familial
Maternal
39603091
Alessandro De Falco et al. ()
c.3196-1G>C
p.?
splice_site_variant
Familial
Maternal
39603091
Alessandro De Falco et al. ()
c.3106C>T
XP_005265353.1:p.Arg1036Trp
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.3107G>A
XP_005265353.1:p.Arg1036Gln
missense_variant
Unknown
33004838
Wang T et al. (2020)
c.847del
p.Arg283GlyfsTer4
frameshift_variant
De novo
39603091
Alessandro De Falco et al. ()
c.1282C>T
p.Pro428Ser
missense_variant
Unknown
37943464
Karthika Ajit Valaparambil et al. ()
c.959del
p.Lys320AsnfsTer15
frameshift_variant
De novo
Simplex
32793091
Crippa M et al. (2020)
c.1206T>A
p.Cys402Ter
stop_gained
Familial
Maternal
Multiplex
40265665
Nora C Callahan et al. ()
c.4103C>T
p.Thr1368Ile
missense_variant
Familial
Paternal
40731902
Vittoria Greco et al. (2025)
c.848G>A
p.Arg283Gln
missense_variant
Familial
Maternal
39603091
Alessandro De Falco et al. ()
c.3855dup
p.Ser1286LeufsTer37
frameshift_variant
De novo
Simplex
28549204
Stur E , et al. (2017)
c.2154del
p.Val719LeufsTer18
frameshift_variant
De novo
Unknown
33619735
Brunet T et al. (2021)
c.1866C>G
p.Tyr622Ter
stop_gained
Unknown
Not maternal
Simplex
24680889
Grozeva D , et al. (2014)
c.2918C>G
p.Ser973Ter
stop_gained
Familial
Paternal
Multiplex
27375234
Szczauba K , et al. (2016)
c.1015del
p.Asp339MetfsTer25
frameshift_variant
De novo
39603091
Alessandro De Falco et al. ()
c.1689del
p.Glu564AsnfsTer22
frameshift_variant
De novo
39603091
Alessandro De Falco et al. ()
c.3195+1G>T
p.?
splice_site_variant
Familial
Paternal
Multiplex
40265665
Nora C Callahan et al. ()
c.31A>G
p.Thr11Ala
missense_variant
Familial
Paternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.3856del
p.Ser1286LeufsTer84
frameshift_variant
De novo
39603091
Alessandro De Falco et al. ()
c.4106dup
p.Ser1370GlufsTer10
frameshift_variant
De novo
39603091
Alessandro De Falco et al. ()
c.2291delC
p.Pro764LeufsTer22
frameshift_variant
De novo
39603091
Alessandro De Falco et al. ()
c.3855dup
p.Ser1286LeufsTer37
frameshift_variant
De novo
Simplex
38764027
Ruohao Wu et al. (2024)
c.2212_2213delAT
p.Met738ValfsTer27
frameshift_variant
Unknown
40265665
Nora C Callahan et al. ()
c.1333C>T
p.Arg445Ter
stop_gained
Unknown
Not maternal
Multiplex
24680889
Grozeva D , et al. (2014)
c.1374A>T
p.Ser458=
missense_variant
Familial
Paternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.71+1947_71+1948insA
frameshift_variant
Familial
Maternal
Simplex
28881385
Powis Z , et al. (2017)
c.3771dup
p.Ser1258GlufsTer65
frameshift_variant
De novo
Simplex
24680889
Grozeva D , et al. (2014)
c.3856del
p.Ser1286LeufsTer84
frameshift_variant
De novo
Simplex
24680889
Grozeva D , et al. (2014)
c.2025_2026del
p.Gly676ValfsTer2
frameshift_variant
De novo
Simplex
31656537
Fang YL , et al. (2019)
c.1550C>T
p.Ala517Val
missense_variant
Familial
Maternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.1712G>C
p.Gly571Ala
missense_variant
Familial
Paternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.2006G>C
p.Gly669Ala
missense_variant
Familial
Maternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.2006G>C
p.Gly669Ala
missense_variant
Familial
Paternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.2348G>A
p.Arg783His
missense_variant
Familial
Maternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.2348G>A
p.Arg783His
missense_variant
Familial
Paternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.2468A>G
p.Asp823Gly
missense_variant
Familial
Maternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.2653T>C
p.Tyr885His
missense_variant
Familial
Maternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.1573_1574del
p.Leu525ArgfsTer17
frameshift_variant
De novo
Simplex
32793091
Crippa M et al. (2020)
c.3174G>C
p.Gln1058His
missense_variant
Familial
Maternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.3817A>C
p.Ser1273Arg
missense_variant
Familial
Maternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.4081G>T
p.Val1361Phe
missense_variant
Familial
Paternal
Simplex
25363760
De Rubeis S , et al. (2014)
c.2955T>A
p.Tyr985Ter
stop_gained
Familial
Maternal
Multi-generational
28881385
Powis Z , et al. (2017)
c.2006G>C
p.Gly669Ala
missense_variant
Familial
Maternal
Multiplex
25363760
De Rubeis S , et al. (2014)
c.2177_2178del
p.Thr726AsnfsTer39
frameshift_variant
De novo
Simplex
24680889
Grozeva D , et al. (2014)
c.4115C>T
p.Thr1372Ile
missense_variant
Familial
Paternal
Multiplex
25363760
De Rubeis S , et al. (2014)
c.2177_2178del
p.Thr726AsnfsTer39
frameshift_variant
Unknown
Simplex
37541188
Sanchis-Juan A et al. (2023)
c.3531_3534del
p.Gly1179AlafsTer10
frameshift_variant
De novo
Simplex
31981491
Satterstrom FK et al. (2020)
c.3154G>T
p.Gly1052Ter
stop_gained
De novo
Unknown
25533962
Deciphering Developmental Disorders Study (2014)
Common Variants
No common variants reported.
Current Score
Scoring History
3rd Party Scoring
SFARI Gene score
1S
High Confidence, Syndromic
Score Delta: Score remained at
1S
criteria met
See SFARI Gene'scoring criteria
High Confidence
See all Category 1 Genes
We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
Syndromic
See all Category S Genes
The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."
1/1/2021
Score remained at
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).
Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2020
Score remained at
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).
Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
Score remained at
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).
Reports Added
[SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome2020]
1/1/2020
Score remained at
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).
Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
1S
Score remained at
New Scoring Scheme
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).
Reports Added
[A novel mutation in a common pathogenic gene (SETD5) associated with intellectual disability: A case report.2019]
[New Scoring Scheme]
10/1/2018
1S
1S
Score remained at
1S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as autistic in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204). Fernandes et al., 2018 reviewed a total of 42 individuals with SETD5 mutations from 17 publications and determined that ten of these individuals presented with autistic features (23.8%).
Reports Added
[Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.2018]
10/1/2017
1S
1S
Score remained at
1S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID in Grozeva et al., 2014; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760); de novo missense variants in SETD5 had previously been observed in ASD probands from simplex families (Neale et al., 2012; Iossifov et al., 2012). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR ? 0.1, meaning that this gene had a ? 90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). De novo LoF or damaging missense variants in SETD5 have also been identified in multiple individuals with developmental delay, intellectual disability, and/or epilepsy in the absence of ASD (PMIDs 23020937, 25138099, 27334371, 28191889, 28549204).
Reports Added
[Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance.2017]
[Expanding the genetic heterogeneity of intellectual disability.2017]
[Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability.2017]
[Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.2017]
[Exome Pool-Seq in neurodevelopmental disorders.2017]
4/1/2017
1S
1S
Score remained at
1S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05< FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).
Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012]
[De novo gene disruptions in children on the autistic spectrum.2012]
[Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014]
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
[Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012]
[Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region.2013]
[De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disa...2014]
[Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.2014]
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
[Low load for disruptive mutations in autism genes and their biased transmission.2015]
[Mutations in HECW2 are associated with intellectual disability and epilepsy.2016]
[Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016]
[SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.2016]
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
[SETD5 gene variant associated with mild intellectual disability - a case report.2017]
1/1/2017
1S
1S
Score remained at
1S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05 < FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).
Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
10/1/2016
1S
1S
Score remained at
1S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05
Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
7/1/2016
1S
1S
Score remained at
1S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05
Reports Added
[Mutations in HECW2 are associated with intellectual disability and epilepsy.2016]
[Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016]
[SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.2016]
1/1/2016
1S
1S
Score remained at
1S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05
Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012]
[De novo gene disruptions in children on the autistic spectrum.2012]
[Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014]
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
[Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012]
[Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region.2013]
[De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disa...2014]
[Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.2014]
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
[Low load for disruptive mutations in autism genes and their biased transmission.2015]
1/1/2015
1S
1S
Score remained at
1S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05
Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
3S
1S
Decreased from
3S
to
1S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05
Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
7/1/2014
No data
3S
Increased from
No data
to
3S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889).
4/1/2014
No data
3S
Increased from
No data
to
3S
Description
Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as âautisticâ in the supplementary material (PMID 24680889).
Krishnan Probability Score
Score
0.49387519752768
Ranking
3940/25841
scored genes
[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning
approach on a human brain-specific gene network. The method was first presented in Nat
Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed
in column G of supplementary table 3 (see:
with the ability to view networks of associated ASD risk genes, can be found at
asd.princeton.edu.
Original Source
ExAC Score
Score
0.99999956377817
Ranking
259/18225
scored genes
[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has
been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by
Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at
exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of-
function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of-
function mutations in autism in such a gene would be more likely to confer risk. For a full list of
pLI scores see:
ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle
aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score
Score
0.903
Ranking
136/239
scored genes
[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists
239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This
probability metric combines the evidence from de novo likely-gene- disrupting and missense
mutations and assesses it against the background mutation rate in unaffected individuals from the
University of Washingtonâs Exome Variant Sequence database (evs.gs.washington.edu/EVS/).
The list of probability scores can be found here:
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/-
/DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score
Score
0.0025046092460738
Ranking
22/18665
scored genes
[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013),
and is a statistic that integrates evidence from both de novo and transmitted mutations.
It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233
(2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper
(the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score
Score
62
Ranking
26/461
scored genes
[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.
Original Source
Zhang D Score
Score
-0.063610089782681
Ranking
10921/20870
scored genes
[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures),
or D score, was developed to combine evidence from de novo loss-of- function mutation with
evidence from cell-type- specific gene expression in the mouse brain (specifically translational
profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with
positive D scores are more likely to be associated with autism risk, with higher-confidence genes
having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204-
215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in
supplementary table 2 from that paper.
Original Source
Interactome
Protein Binding
DNA Binding
RNA Binding
Protein Modification
Direct Regulation
ASD-Linked Genes
Interaction Table
Interactor Symbol
Interactor Name
Interactor Organism
Interactor Type
Entrez ID
Uniprot ID
CEP70
centrosomal protein 70kDa
Human
Protein Binding
80321
Q8NHQ1
DPPA2
Developmental pluripotency-associated protein 2
Human
Protein Binding
151871
Q7Z7J5
miR126-5p
microRNA 126
Human
RNA Binding
406913
N/A
miR1265p
microRNA 126
Human
RNA Binding
406913
N/A
PRR20E
Proline-rich protein 20E
Human
Protein Binding
122183
P86478
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