Human Gene Module / Chromosome 22 / SGSM3

SGSM3Small G protein signaling modulator 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
11 / 0
Aliases
SGSM3, RP5-1042K10.9,  MAP,  RABGAP5,  RUSC3,  RUTBC3,  RabGAP-5
Associated Syndromes
-
Chromosome Band
22q13.1
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

May play a cooperative role in NF2-mediated growth suppression of cells.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SGSM3 (8 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 Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
4 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
5 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
6 Support - Woodbury-Smith M et al. (2022) Yes -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Rivka Birnbaum et al. (2024) No ADHD, ID
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.376C>T p.Arg126Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1256G>A p.Arg419Gln missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.701C>T p.Ala234Val missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1108C>T p.Arg370Cys missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.1931A>G p.Asp644Gly missense_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.996+2T>C - splice_site_variant Familial Paternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.1586+1G>A - splice_site_variant Familial Paternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.792dup p.Glu265ArgfsTer90 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1680G>T p.Val560= synonymous_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.981dup p.Glu328ArgfsTer90 frameshift_variant Familial Both parents Simplex 37833060 Rivka Birnbaum et al. (2024)
c.981dup p.Glu328ArgfsTer90 frameshift_variant Familial Both parents Multiplex 37833060 Rivka Birnbaum et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo missense variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). Paternally-transmitted splice-site variants in SGSM3 were observed in two unrelated ASD probands from the Simons Simplex Collection (PMID 23160955).

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

De novo missense variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). Paternally-transmitted splice-site variants in SGSM3 were observed in two unrelated ASD probands from the Simons Simplex Collection (PMID 23160955).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

De novo missense variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). Paternally-transmitted splice-site variants in SGSM3 were observed in two unrelated ASD probands from the Simons Simplex Collection (PMID 23160955).

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

Decreased from 4 to 4

Description

De novo missense variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). Paternally-transmitted splice-site variants in SGSM3 were observed in two unrelated ASD probands from the Simons Simplex Collection (PMID 23160955).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

De novo missense variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). Paternally-transmitted splice-site variants in SGSM3 were observed in two unrelated ASD probands from the Simons Simplex Collection (PMID 23160955).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
7/1/2015
icon
4

Increased from to 4

Description

De novo missense variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955). Paternally-transmitted splice-site variants in SGSM3 were observed in two unrelated ASD probands from the Simons Simplex Collection (PMID 23160955).

Krishnan Probability Score

Score 0.40895816445906

Ranking 22884/25841 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 1.0060127115481E-6

Ranking 15028/18225 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 0.59238060635233

Ranking 684/18665 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 14

Ranking 140/461 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 0.45804033216151

Ranking 850/20870 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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