Human Gene Module / Chromosome 3 / SETD2

SETD2SET domain containing 2

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
8 / 12
Rare Variants / Common Variants
14 / 0
Aliases
SETD2, HSPC069,  HBP231,  HIF-1,  HIP-1,  HYPB,  KMT3A,  SET2,  p231HBP
Associated Syndromes
Luscan-Lumish syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
3p21.31
Associated Disorders
ASD, ID, DD/NDD
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.

Reports related to SETD2 (11 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 -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
G>T p.Lys610O missense_variant Unknown - Multiplex 25574603 Butler MG , et al. (2015)
c.1986A>G p.Gln662%3D synonymous_variant De novo NA - 24463507 Fromer M , et al. (2014)
c.19C>T p.Gln7Ter stop_gained Familial Maternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.121A>T p.Ile41Phe missense_variant De novo NA 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.1182T>A p.Cys394Ter stop_gained Familial Paternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.2028del p.Pro677LeufsTer19 frameshift_variant De novo NA Simplex 26084711 Lumish HS , et al. (2015)
c.6341del p.Asn2114IlefsTer33 frameshift_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.7356dup p.Lys2453GlufsTer13 frameshift_variant De novo NA Multiplex 31398340 Ruzzo EK , et al. (2019)
c.6422del p.Gly2141GlufsTer63 frameshift_variant De novo NA Simplex 29681085 van Rij MC , et al. (2018)
- p.Ser2060Pro missense_variant Familial Paternal Multi-generational 26845707 Alvarez-Mora MI , et al. (2016)
c.1462_1482delinsAC p.Ser488ThrfsTer41 frameshift_variant De novo NA Simplex 29681085 van Rij MC , et al. (2018)
CTTCTTTCT>CTTCT - frameshift_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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).

Score Delta: Decreased from 3 to 1

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.

10/1/2019
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
[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).

4/1/2018
3
icon
3.3

Decreased from 3 to 3.3

Description

3

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).

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).

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).

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.
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
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).
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.
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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
F9 Coagulation factor IX Human Protein Binding 2158 P00740
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We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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