Human Gene Module / Chromosome 22 / SBF1

SBF1SET binding factor 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 11
Rare Variants / Common Variants
12 / 0
Aliases
SBF1, C22:RP4-579N16.2,  DENND7A,  MTMR5
Associated Syndromes
Charcot-Marie-Tooth syndrome
Chromosome Band
22q13.33
Associated Disorders
-
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)

Molecular Function

This gene encodes a member of the protein-tyrosine phosphatase family. However, the encoded protein does not appear to be a catalytically active phosphatase because it lacks several amino acids in the catalytic pocket. This protein contains a Guanine nucleotide exchange factor (GEF) domain which is necessary for its role in growth and differentiation.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SBF1 (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 Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Support Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families Alazami AM , et al. (2015) No Microcephaly
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
6 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder Alvarez-Mora MI , et al. (2016) Yes -
7 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
8 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations Zhou WZ , et al. (2019) Yes -
9 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
10 Support - Kim IB et al. (2022) Yes -
11 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.791+7C>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.1180G>T p.Glu394Ter stop_gained De novo - - 30763456 Zhou WZ , et al. (2019)
c.3010G>A p.Ala1004Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3385G>A p.Asp1129Asn missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2083C>T p.Arg695Trp missense_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.1700G>A p.Arg567His missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.3079A>G p.Thr1027Ala missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.730C>T p.Gln244Ter stop_gained Familial Maternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.2195G>A p.Arg732His missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.5311C>T p.Arg1771Cys missense_variant Familial Both parents Simplex 35840799 Kim IB et al. (2022)
c.1327G>A p.Asp443Asn missense_variant Familial Both parents Multiplex 25558065 Alazami AM , et al. (2015)
c.4857C>G p.Asp1619Glu missense_variant Familial Maternal Multi-generational 26845707 Alvarez-Mora MI , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants and an inherited nonsense variant in the SBF1 gene have been observed in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo missense variants and an inherited nonsense variant in the SBF1 gene have been observed in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants and an inherited nonsense variant in the SBF1 gene have been observed in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

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

Decreased from 3 to 3

Description

Two de novo missense variants and an inherited nonsense variant in the SBF1 gene have been observed in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018] [Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]
1/1/2016
icon
3

Increased from to 3

Description

Two de novo missense variants and an inherited nonsense variant in the SBF1 gene have been observed in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

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] [Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016]
Krishnan Probability Score

Score 0.49109951858745

Ranking 5801/25841 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 0.69053881388738

Ranking 4524/18225 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 0.961

Ranking 71/239 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 0.74142374772535

Ranking 1473/18665 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 10

Ranking 192/461 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 0.29073797282844

Ranking 2872/20870 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
HENMT1 Small RNA 2'-O-methyltransferase Human Protein Binding 113802 Q5T8I9
RAB6B Ras-related protein Rab-6B Human Protein Binding 51560 Q9NRW1
SKAP1 Src kinase-associated phosphoprotein 1 Human Protein Binding 8631 Q86WV1-2
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