Human Gene Module / Chromosome 1 / SETDB1

SETDB1SET domain, bifurcated 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
16 / 0
Aliases
SETDB1, RP11-316M1.1,  ESET,  H3-K9-HMTase4,  KG1T,  KMT1E
Associated Syndromes
-
Chromosome Band
1q21.3
Associated Disorders
-
Relevance to Autism

A total of nine ASD-specific variants in the SETDB1 gene were identified in cases but not controls. One of these variants, SETDB1 Pro1067del, segregated with disease in a multiplex ASD family (Cukier et al., 2012). An additional missense variant in SETDB1, p.Pro529Leu, was enriched in ASD cases of European ancestry(5/202 cases vs. 1/198 controls).

Molecular Function

Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3, which represents a specific tag for epigenetic transcriptional repression. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SETDB1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1 Cukier HN , et al. (2012) Yes -
2 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
3 Recent Recommendation The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain Jiang Y , et al. (2017) No -
4 Support - Balan S et al. (2021) Yes -
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.876-7T>C - splice_region_variant Unknown - - 34262135 Balan S et al. (2021)
c.2988T>C p.Phe996%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3123G>T p.Lys1041Asn missense_variant Unknown - - 34262135 Balan S et al. (2021)
c.-107C>T - intron_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.447+1G>C - intron_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.1424+13C>T - intron_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.3159-17C>T - intron_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.561G>T p.Gln187His missense_variant Familial Maternal - 34262135 Balan S et al. (2021)
c.3292-108A>G - intron_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.2366C>G p.Pro789Arg missense_variant Familial Paternal - 34262135 Balan S et al. (2021)
c.3732C>G p.Arg1244= missense_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.924G>A p.Ser308= synonymous_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.3772G>T p.Ala1258Ser synonymous_variant Unknown Unknown Unknown 23055267 Cukier HN , et al. (2012)
c.3200del p.Pro1067LeufsTer2 inframe_deletion Familial Maternal Multiplex 23055267 Cukier HN , et al. (2012)
c.262G>A p.Ala88Thr missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1586C>T p.Pro529Leu missense_variant Familial Maternal (4 cases), paternal (1 case) Simplex 23055267 Cukier HN , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A total of nine ASD-specific variants in the SETDB1 gene were identified in cases but not controls. One of these variants, SETDB1 Pro1067del, segregated with disease in a multiplex ASD family (Cukier et al., 2012). An additional missense variant in SETDB1, p.Pro529Leu, was enriched in ASD cases of European ancestry (5/202 cases vs. 1/198 controls).

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A total of nine ASD-specific variants in the SETDB1 gene were identified in cases but not controls. One of these variants, SETDB1 Pro1067del, segregated with disease in a multiplex ASD family (Cukier et al., 2012). An additional missense variant in SETDB1, p.Pro529Leu, was enriched in ASD cases of European ancestry (5/202 cases vs. 1/198 controls).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A total of nine ASD-specific variants in the SETDB1 gene were identified in cases but not controls. One of these variants, SETDB1 Pro1067del, segregated with disease in a multiplex ASD family (Cukier et al., 2012). An additional missense variant in SETDB1, p.Pro529Leu, was enriched in ASD cases of European ancestry (5/202 cases vs. 1/198 controls).

Reports Added
[New Scoring Scheme]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

A total of nine ASD-specific variants in the SETDB1 gene were identified in cases but not controls. One of these variants, SETDB1 Pro1067del, segregated with disease in a multiplex ASD family (Cukier et al., 2012). An additional missense variant in SETDB1, p.Pro529Leu, was enriched in ASD cases of European ancestry (5/202 cases vs. 1/198 controls).

Reports Added
[The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain.2017]
7/1/2015
icon
4

Increased from to 4

Description

A total of nine ASD-specific variants in the SETDB1 gene were identified in cases but not controls. One of these variants, SETDB1 Pro1067del, segregated with disease in a multiplex ASD family (Cukier et al., 2012). An additional missense variant in SETDB1, p.Pro529Leu, was enriched in ASD cases of European ancestry (5/202 cases vs. 1/198 controls).

Krishnan Probability Score

Score 0.4920610304447

Ranking 4775/25841 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 0.99999668396948

Ranking 373/18225 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 0.94887832789854

Ranking 17863/18665 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 20

Ranking 104/461 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 0.26583477731721

Ranking 3245/20870 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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