Human Gene Module / Chromosome 12 / SETD1B

SETD1BSET domain containing 1B

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
8 / 20
Rare Variants / Common Variants
56 / 0
Aliases
SETD1B, KMT2G,  Set1B
Associated Syndromes
12q24.31 microdeletion syndrome
Chromosome Band
12q24.31
Associated Disorders
ADHD, ASD
Relevance to Autism

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

Molecular Function

SET1B is a component of a histone methyltransferase complex that produces trimethylated histone H3 at Lys4; H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SETD1B (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A microdeletion at 12q24.31 can mimic beckwith-wiedemann syndrome neonatally Baple E , et al. (2010) No -
2 Support Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability Qiao Y , et al. (2012) No -
3 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Microdeletion of 12q24.31: report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms Palumbo O , et al. (2014) No -
5 Support An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability Labonne JD , et al. (2016) No -
6 Recent Recommendation De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism Hiraide T , et al. (2018) Yes -
7 Support A novel de novo frameshift variant in SETD1B causes epilepsy Den K , et al. (2019) No Autistic features
8 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
9 Support De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences Hiraide T , et al. (2019) Yes -
10 Support - Krzyzewska IM et al. (2019) No -
11 Support SETD1B-associated neurodevelopmental disorder Roston A et al. (2020) No ASD, ADHD
12 Support - Brunet T et al. (2021) Yes -
13 Support - Hiraide T et al. (2021) Yes -
14 Recent Recommendation - Weerts MJA et al. (2021) No ASD or autistic features
15 Support - Michurina A et al. (2021) No -
16 Support - Álvarez-Mora MI et al. (2022) No -
17 Support - Brea-Fernández AJ et al. (2022) No -
18 Support - Zhou X et al. (2022) Yes -
19 Support - Balasar et al. (2023) No Autistic features
20 Support - et al. () Yes ADHD, BPD, OCD, ID, learning disability
Rare Variants   (56)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - missense_variant De novo - Simplex 32546566 Roston A et al. (2020)
c.2932C>T p.Gln978Ter stop_gained De novo - - 32546566 Roston A et al. (2020)
c.5589+1G>A - splice_site_variant De novo - Simplex 32546566 Roston A et al. (2020)
c.282G>C p.Glu94Asp missense_variant Familial - - 34345025 Weerts MJA et al. (2021)
c.1634C>G p.Pro545Arg missense_variant Unknown - - 34345025 Weerts MJA et al. (2021)
c.2945G>A p.Arg982Gln missense_variant Unknown - - 34345025 Weerts MJA et al. (2021)
c.30C>A p.His10Gln missense_variant Familial Maternal Multiplex 38256266 et al. ()
c.22del p.His8ThrfsTer27 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.3964C>T p.Gln1322Ter stop_gained De novo - Simplex 32546566 Roston A et al. (2020)
c.5524C>T p.Arg1842Trp missense_variant De novo - - 29322246 Hiraide T , et al. (2018)
c.5575C>T p.Gln1859Ter missense_variant De novo - - 29322246 Hiraide T , et al. (2018)
c.3982C>T p.Pro1328Ser missense_variant Familial - - 34345025 Weerts MJA et al. (2021)
c.3985C>T p.Arg1329Ter stop_gained De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.4570C>T p.Arg1524Ter stop_gained De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.4996C>T p.Gln1666Ter stop_gained De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5407C>T p.Arg1803Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.30C>A p.His10Gln missense_variant Familial - Simplex 34345025 Weerts MJA et al. (2021)
c.3807T>C p.Pro1269%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5415G>A p.Leu1805%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4577C>T p.Pro1526Leu missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5699A>G p.Tyr1900Cys missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.5704C>T p.Arg1902Cys missense_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.386T>G p.Val129Gly missense_variant De novo - Simplex 31440728 Hiraide T , et al. (2019)
c.509T>C p.Met170Thr missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.584G>T p.Gly195Val missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.1071C>T p.Val357%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5704C>T p.Arg1902Cys missense_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.1285C>T p.Arg429Trp missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.2092C>T p.Pro698Ser missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.2378C>G p.Pro793Arg missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.288del p.Tyr96Ter frameshift_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.1658G>A p.Gly553Asp missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.842C>T p.Thr281Ile missense_variant Familial Paternal - 34345025 Weerts MJA et al. (2021)
c.2780G>A p.Arg927His missense_variant Familial - Simplex 34345025 Weerts MJA et al. (2021)
c.3884C>T p.Pro1295Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3029C>T p.Ala1010Val missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.3386C>T p.Ala1129Val missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.4271G>A p.Arg1424Gln missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5242C>T p.Arg1748Cys missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5374C>T p.Arg1792Trp missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5474G>C p.Arg1825Pro missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5480A>G p.Lys1827Arg missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5702C>A p.Ala1901Glu missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5702C>T p.Ala1901Val missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5842G>A p.Glu1948Lys missense_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.3772C>T p.Arg1258Ter stop_gained De novo - Simplex 35183220 Álvarez-Mora MI et al. (2022)
c.22dup p.His8ProfsTer30 frameshift_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5184_5185del p.Ala1730Ter frameshift_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.284_286delinsA p.Phe95Ter frameshift_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.5645_5648del p.Tyr1882CysfsTer34 frameshift_variant De novo - Simplex 31110234 Den K , et al. (2019)
c.1234del p.Glu412LysfsTer96 frameshift_variant Familial Maternal - 34345025 Weerts MJA et al. (2021)
c.953C>T p.Thr318Met missense_variant Familial Both parents Multiplex 34345025 Weerts MJA et al. (2021)
c.5820_5826del p.Tyr1941IlefsTer101 frameshift_variant De novo - Simplex 34345025 Weerts MJA et al. (2021)
c.3026_3048del p.Leu1009ArgfsTer88 frameshift_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.5690_5695del p.Thr1897_Asp1899delinsAsn inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
c.337_363inv p.Asn113_Asp121delinsValProGlnGluValPheThrAspVal inversion De novo - Simplex 34345025 Weerts MJA et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

Score Delta: Score remained at 2S

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.

S

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."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

1/1/2021
3S
icon
3S

Decreased from 3S to 3S

Description

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021] [Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
7/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

Reports Added
[SETD1B-associated neurodevelopmental disorder2020]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

Reports Added
[A novel de novo frameshift variant in SETD1B causes epilepsy.2019] [Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019] [De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences.2019]
7/1/2018
icon
4S

Increased from to 4S

Description

Two de novo variants in the SETD1B gene (an inframe deletion variant and a missense variant) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. SETD1B has been implicated as a candidate gene in 12q24.31 microdeletion syndrome, a disorder characterized by intellectual disability, autism/autistic features, epilepsy, and facial dysmorphic features (Baple et al., 2010; Qiao et al., 2013; Palumbo et al., 2015; Labonne et al., 2016). Hiraide et al., 2018 identified two individuals with novel de novo SETD1B missense variants, both of whom were diagnosed with autism/ASD and presented with intellectual disability, language delay, and epilepsy.

Krishnan Probability Score

Score 0.46887493608937

Ranking 8996/25841 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 0.02245631589155

Ranking 9299/18225 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 0.833

Ranking 210/239 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 Washington’s 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 0.94759847786217

Ranking 17341/18665 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 0.32667589781349

Ranking 2335/20870 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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