Human Gene Module / Chromosome 3 / SETD2

SETD2SET domain containing 2

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
17 / 27
Rare Variants / Common Variants
70 / 0
Aliases
SETD2, HSPC069,  HBP231,  HIF-1,  HIP-1,  HYPB,  KMT3A,  SET2,  p231HBP
Associated Syndromes
Luscan-Lumish syndrome, Luscan-Lumish syndrome, DD
Chromosome Band
3p21.31
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Relevance to Autism

De novo variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (Sanders et al. 2012a, 2012b). A second de novo LoF variant in this gene was identified in a female patient presenting with ASD, developmental delay, ID, seizures, Chiari I malformation, macrocephaly, and short stature(Lumish et al., 2015).

Molecular Function

Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SETD2 (27 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
2 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders O'Roak BJ , et al. (2012) Yes -
3 Support De novo mutations in schizophrenia implicate synaptic networks Fromer M , et al. (2014) Yes -
4 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
5 Support Whole exome sequencing in females with autism implicates novel and candidate genes Butler MG , et al. (2015) Yes -
6 Support Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy Lumish HS , et al. (2015) Yes Macrocephaly
7 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms D'Gama AM , et al. (2015) Yes -
8 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder Alvarez-Mora MI , et al. (2016) Yes -
9 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia Takata A , et al. (2016) No -
10 Support Two novel cases expanding the phenotype of SETD2-related overgrowth syndrome van Rij MC , et al. (2018) No ASD or autistic behavior
11 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
12 Support SETD2 related overgrowth syndrome: Presentation of four new patients and review of the literature Marzin P , et al. (2019) No ASD, DD, ID, macrocepahly
13 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
14 Support Genotype-phenotype correlation at codon 1740 of SETD2 Rabin R et al. (2020) No Epilepsy/seizures
15 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
16 Support - Pode-Shakked B et al. (2021) No -
17 Support - Woodbury-Smith M et al. (2022) Yes -
18 Support - Zhou X et al. (2022) Yes -
19 Support - More RP et al. (2023) Yes -
20 Support - Zhang Y et al. (2023) No -
21 Support - Wu Y et al. (2023) No -
22 Support - Parra A et al. (2023) Yes ADHD, epilepsy/seizures
23 Support - Cirnigliaro M et al. (2023) Yes -
24 Support - Sheth F et al. (2023) Yes DD, ID
25 Support - Ana Karen Sandoval-Talamantes et al. (2023) Yes ID
26 Support - Tamam Khalaf et al. (2024) No -
27 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (70)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.19C>T p.Gln7Ter stop_gained Unknown - - 37372360 Parra A et al. (2023)
c.4583+1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.3651G>A p.Trp1217Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.4783G>T p.Glu1595Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.3439C>T p.Gln1147Ter stop_gained De novo - - 37372360 Parra A et al. (2023)
c.3964C>T p.Arg1322Ter stop_gained De novo - - 37372360 Parra A et al. (2023)
c.4276A>T p.Lys1426Ter stop_gained Unknown - - 31643139 Marzin P , et al. (2019)
c.6471T>A p.Tyr2157Ter stop_gained De novo - - 31643139 Marzin P , et al. (2019)
c.4649C>T p.Ala1550Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5057G>A p.Arg1686Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5218C>T p.Arg1740Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6161C>T p.Pro2054Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6394C>T p.Arg2132Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6997G>A p.Gly2333Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7429G>A p.Glu2477Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.19C>T p.Gln7Ter stop_gained Familial Maternal - 37372360 Parra A et al. (2023)
c.2687C>T p.Thr896Ile missense_variant De novo - - 37372360 Parra A et al. (2023)
c.1540C>A p.Leu514Ile frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1986A>G p.Gln662%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5086C>T p.Arg1696Trp missense_variant De novo - - 32710489 Rabin R et al. (2020)
c.5087G>A p.Arg1696Gln missense_variant De novo - - 32710489 Rabin R et al. (2020)
c.5218C>T p.Arg1740Trp missense_variant De novo - - 32710489 Rabin R et al. (2020)
c.5219G>A p.Arg1740Gln missense_variant De novo - - 32710489 Rabin R et al. (2020)
c.4586G>C p.Cys1529Ser missense_variant De novo - - 37372360 Parra A et al. (2023)
c.5152G>A p.Glu1718Lys missense_variant De novo - - 37372360 Parra A et al. (2023)
c.6299A>G p.Asp2100Gly missense_variant Unknown - - 37372360 Parra A et al. (2023)
c.6753C>G p.Asp2251Glu missense_variant De novo - - 37372360 Parra A et al. (2023)
c.7624G>A p.Glu2542Lys missense_variant De novo - - 37372360 Parra A et al. (2023)
c.5761G>T p.Glu1921Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.4341C>T p.Pro1447%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.7534-1G>T - splice_site_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1986A>G p.Gln662= synonymous_variant De novo - - 24463507 Fromer M , et al. (2014)
c.4997A>G p.Tyr1666Cys missense_variant De novo - - 31643139 Marzin P , et al. (2019)
G>T p.Lys610O missense_variant Unknown - Multiplex 25574603 Butler MG , et al. (2015)
c.97G>A p.Glu33Lys missense_variant Familial Maternal - 37372360 Parra A et al. (2023)
c.4120A>G p.Ser1374Gly missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.1539del p.Lys513AsnfsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.4801C>T p.Gln1601Ter stop_gained De novo - Multiplex 32094338 Husson T , et al. (2020)
c.-98C>T - stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4210del p.Arg1407GlyfsTer5 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.121A>T p.Ile41Phe missense_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.614C>T p.Ser205Phe missense_variant Familial - Multiplex 36702863 More RP et al. (2023)
c.1463A>G p.Tyr488Cys missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3769A>T p.Asn1257Tyr missense_variant Familial Paternal - 37372360 Parra A et al. (2023)
c.6789dup p.Val2264CysfsTer61 frameshift_variant Unknown - - 37372360 Parra A et al. (2023)
c.1415G>A p.Arg472His missense_variant Familial - Multiplex 36702863 More RP et al. (2023)
c.19C>T p.Gln7Ter stop_gained Familial Maternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.1463A>G p.Tyr488Cys missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.4686C>G p.Phe1562Leu missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.1669_1673del p.Ser557ProfsTer9 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2382_2384del p.Ser794del inframe_deletion De novo - Simplex 36777730 Zhang Y et al. (2023)
c.7089C>G p.Pro2363%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1717_1720del p.Phe573ValfsTer5 frameshift_variant De novo - - 37372360 Parra A et al. (2023)
c.1182T>A p.Cys394Ter stop_gained Familial Paternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.4457_4460del p.Lys1486ArgfsTer28 frameshift_variant Unknown - - 37372360 Parra A et al. (2023)
c.4689G>A p.Met1563Ile missense_variant Unknown Not maternal - 31643139 Marzin P , et al. (2019)
c.1552T>C p.Ser518Pro missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.5700_5703dup p.Ala1902ArgfsTer3 frameshift_variant De novo - Simplex 37025455 Wu Y et al. (2023)
c.5282_5299del p.Thr1761_Leu1767delinsMet inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.2028del p.Pro677LeufsTer19 frameshift_variant De novo - Simplex 26084711 Lumish HS , et al. (2015)
c.6341del p.Asn2114IlefsTer33 frameshift_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.2598_2615del p.His866_Tyr871del inframe_deletion Familial Paternal - 37372360 Parra A et al. (2023)
c.7356dup p.Lys2453GlufsTer13 frameshift_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.6422del p.Gly2141GlufsTer63 frameshift_variant De novo - Simplex 29681085 van Rij MC , et al. (2018)
c.6299A>G p.Asp2100Gly missense_variant Unknown - - 38003033 Ana Karen Sandoval-Talamantes et al. (2023)
c.7409_7410insAC p.His2470GlnfsTer5 frameshift_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.1748_1751del p.Lys583SerfsTer17 frameshift_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.1462_1482delinsAC p.Ser488ThrfsTer41 frameshift_variant De novo - Simplex 29681085 van Rij MC , et al. (2018)
CTTCTTTCT>CTTCT - frameshift_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.6178T>C p.Ser2060Pro missense_variant Familial Paternal Multi-generational 26845707 Alvarez-Mora MI , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

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.

10/1/2020
1
icon
1

Score remained at 1

Description

De novo LoF variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LoF variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955). More recently, a second de novo LoF variant in this gene was identified in a female patient with ASD, developmental delay, ID, seizures, Chiari I malformation, and macrocephaly (PMID 26084711).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
1
icon
1

Score remained at 1

Description

De novo LoF variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LoF variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955). More recently, a second de novo LoF variant in this gene was identified in a female patient with ASD, developmental delay, ID, seizures, Chiari I malformation, and macrocephaly (PMID 26084711).

Reports Added
[Genotype-phenotype correlation at codon 1740 of SETD22020]
1/1/2020
1
icon
1

Score remained at 1

Description

De novo LoF variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LoF variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955). More recently, a second de novo LoF variant in this gene was identified in a female patient with ASD, developmental delay, ID, seizures, Chiari I malformation, and macrocephaly (PMID 26084711).

Reports Added
[Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

De novo LoF variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LoF variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955). More recently, a second de novo LoF variant in this gene was identified in a female patient with ASD, developmental delay, ID, seizures, Chiari I malformation, and macrocephaly (PMID 26084711).

Reports Added
[SETD2 related overgrowth syndrome: Presentation of four new patients and review of the literature.2019] [New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

De novo LoF variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LoF variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955). More recently, a second de novo LoF variant in this gene was identified in a female patient with ASD, developmental delay, ID, seizures, Chiari I malformation, and macrocephaly (PMID 26084711).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2016
3
icon
3

Decreased from 3 to 3

Description

De novo LoF variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LoF variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955). More recently, a second de novo LoF variant in this gene was identified in a female patient with ASD, developmental delay, ID, seizures, Chiari I malformation, and macrocephaly (PMID 26084711).

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Whole exome sequencing in females with autism implicates novel and candidate genes.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [De novo mutations in schizophrenia implicate synaptic networks.2014] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

De novo LoF variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LoF variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955). More recently, a second de novo LoF variant in this gene was identified in a female patient with ASD, developmental delay, ID, seizures, Chiari I malformation, and macrocephaly (PMID 26084711).

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Whole exome sequencing in females with autism implicates novel and candidate genes.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016]
7/1/2015
4
icon
3

Decreased from 4 to 3

Description

De novo LoF variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LoF variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955). More recently, a second de novo LoF variant in this gene was identified in a female patient with ASD, developmental delay, ID, seizures, Chiari I malformation, and macrocephaly (PMID 26084711).

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Whole exome sequencing in females with autism implicates novel and candidate genes.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy.2015]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

De novo LGD variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LGD variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955).

Reports Added
[Whole exome sequencing in females with autism implicates novel and candidate genes.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

De novo LGD variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LGD variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

De novo LGD variant in SETD2 gene identified in simplex ASD case (PMID 22495309); subsequent inherited LGD variants and a de novo missense variant identified in three other simplex ASD cases (PMID 23160955).

Krishnan Probability Score

Score 0.49414251857921

Ranking 3812/25841 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: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99999294407418

Ranking 424/18225 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
Sanders TADA Score

Score 0.62352516089134

Ranking 791/18665 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 18

Ranking 116/461 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 0.46266618232744

Ranking 804/20870 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
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
F9 Coagulation factor IX Human Protein Binding 2158 P00740
Submit New Gene

Report an Error