Human Gene Module / Chromosome 9 / SET

SETSETnuclear proto-oncogene

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 6
Rare Variants / Common Variants
12 / 0
EAGLE Score
4
Limited Learn More
Aliases
SET, 2PP2A,  I2PP2A,  IGAAD,  IPP2A2,  MRD58,  PHAPII,  TAF-I,  TAF-IBETA
Associated Syndromes
-
Chromosome Band
9q34.11
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation
Relevance to Autism

De novo likely gene-disruptive (LGD) variants in the SET gene have been identifed in two probands with ASD (Yuen et al., 2017) and three probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SET as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) that passed a Bonferroni family-wise error rare (FWER) correction indicating exome-wide significance (P < 5.0E-07); SET was similarly identified as a gene with an excess of de novo LGD variants (false discovery rata < 5%, count >1) following analysis of 5,624 cases with a primary diagnosis of ASD (Coe et al., 2018). Stevens et al., 2018 identified four individuals with de novo SET variants, as well as an affected mother and son with a SET frameshift variant, who presented with non-syndromic intellectual disability (autosomal dominant mental retardation-58; OMIM 618106).

Molecular Function

The protein encoded by this gene inhibits acetylation of nucleosomes, especially histone H4, by histone acetylases (HAT). This inhibition is most likely accomplished by masking histone lysines from being acetylated, and the consequence is to silence HAT-dependent transcription. Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SET (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
2 Primary Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability Stevens SJC , et al. (2018) No -
4 Recent Recommendation Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity Coe BP , et al. (2018) No -
5 Support - Brunet T et al. (2021) No -
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.417+1G>C - splice_site_variant De novo - - 29688601 Stevens SJC , et al. (2018)
c.112+1G>C - splice_site_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.283T>G p.Trp95Gly missense_variant De novo - - 29688601 Stevens SJC , et al. (2018)
c.352C>T p.His118Tyr missense_variant De novo - - 29688601 Stevens SJC , et al. (2018)
c.164_167del p.Ile55ThrfsTer12 frameshift_variant De novo - - 28135719 et al. (2017)
c.167_170del p.Arg57LeufsTer10 frameshift_variant De novo - - 28135719 et al. (2017)
c.459_460del p.Lys154ArgfsTer6 frameshift_variant De novo - - 28135719 et al. (2017)
c.391_392del p.Ile131Ter splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.112G>C p.Glu38Gln splice_site_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.689_690dup p.Gln231TyrfsTer29 frameshift_variant De novo - - 29688601 Stevens SJC , et al. (2018)
c.457_458del p.Ser153GlufsTer23 frameshift_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.167_170del p.Arg57LeufsTer10 frameshift_variant Familial Maternal Simplex 29688601 Stevens SJC , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo likely gene-disruptive (LGD) variants in the SET gene have been identifed in two probands with ASD (Yuen et al., 2017) and three probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SET as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) that passed a Bonferroni family-wise error rare (FWER) correction indicating exome-wide significance (P < 5.0E-07); SET was similarly identified as a gene with an excess of de novo LGD variants (false discovery rata < 5%, count >1) following analysis of 5,624 cases with a primary diagnosis of ASD (Coe et al., 2018). Stevens et al., 2018 identified four individuals with de novo SET variants, as well as an affected mother and son with a SET frameshift variant, who presented with non-syndromic intellectual disability (autosomal dominant mental retardation-58; OMIM 618106).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

1/1/2021
2
icon
2

Score remained at 2

Description

De novo likely gene-disruptive (LGD) variants in the SET gene have been identifed in two probands with ASD (Yuen et al., 2017) and three probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SET as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) that passed a Bonferroni family-wise error rare (FWER) correction indicating exome-wide significance (P < 5.0E-07); SET was similarly identified as a gene with an excess of de novo LGD variants (false discovery rata < 5%, count >1) following analysis of 5,624 cases with a primary diagnosis of ASD (Coe et al., 2018). Stevens et al., 2018 identified four individuals with de novo SET variants, as well as an affected mother and son with a SET frameshift variant, who presented with non-syndromic intellectual disability (autosomal dominant mental retardation-58; OMIM 618106).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
Description

De novo likely gene-disruptive (LGD) variants in the SET gene have been identifed in two probands with ASD (Yuen et al., 2017) and three probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SET as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) that passed a Bonferroni family-wise error rare (FWER) correction indicating exome-wide significance (P < 5.0E-07); SET was similarly identified as a gene with an excess of de novo LGD variants (false discovery rata < 5%, count >1) following analysis of 5,624 cases with a primary diagnosis of ASD (Coe et al., 2018). Stevens et al., 2018 identified four individuals with de novo SET variants, as well as an affected mother and son with a SET frameshift variant, who presented with non-syndromic intellectual disability (autosomal dominant mental retardation-58; OMIM 618106).

Reports Added
[New Scoring Scheme]
1/1/2019
icon
2

Increased from to 2

Description

De novo likely gene-disruptive (LGD) variants in the SET gene have been identifed in two probands with ASD (Yuen et al., 2017) and three probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified SET as a gene with an excess of LGD variants (false discovery rata < 5%, count >1) that passed a Bonferroni family-wise error rare (FWER) correction indicating exome-wide significance (P < 5.0E-07); SET was similarly identified as a gene with an excess of de novo LGD variants (false discovery rata < 5%, count >1) following analysis of 5,624 cases with a primary diagnosis of ASD (Coe et al., 2018). Stevens et al., 2018 identified four individuals with de novo SET variants, as well as an affected mother and son with a SET frameshift variant, who presented with non-syndromic intellectual disability (autosomal dominant mental retardation-58; OMIM 618106).

Krishnan Probability Score

Score 0.73333333333334

Ranking 38/25841 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 0.96336427990367

Ranking 2479/18225 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 0.90299845462318

Ranking 6690/18665 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
Zhang D Score

Score 0.17956287514801

Ranking 4604/20870 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
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