Human Gene Module / Chromosome 3 / SRGAP3

SRGAP3SLIT-ROBO Rho GTPase activating protein 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 6
Rare Variants / Common Variants
8 / 0
Aliases
SRGAP3, ARHGAP14,  MEGAP,  SRGAP2,  WRP
Associated Syndromes
-
Chromosome Band
3p25.3
Associated Disorders
-
Relevance to Autism

Two de novo missense variants in the SRGAP3 gene (one predicted to be probably damaging, the other predicted to be possibly damaging) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014.

Molecular Function

GTPase-activating protein for RAC1 and perhaps Cdc42, but not for RhoA small GTPase. May attenuate RAC1 signaling in neurons.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SRGAP3 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental retardation Endris V , et al. (2002) No -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) No -
4 Recent Recommendation ASD-Associated De Novo Mutations in Five Actin Regulators Show Both Shared and Distinct Defects in Dendritic Spines and Inhibitory Synapses in Cultured Hippocampal Neurons Hlushchenko I , et al. (2018) No -
5 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - Simplex 12195014 Endris V , et al. (2002)
c.74G>T p.Arg25Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2828_2830del p.Thr943del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.1811T>C p.Ile604Thr missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.610C>T p.Arg204Trp missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1627G>T p.Val543Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1405G>A p.Glu469Lys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2329G>A p.Ala777Thr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants in the SRGAP3 gene (one predicted to be probably damaging, the other predicted to be possibly damaging) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. A de novo missense variant that was predicted to be damaging was identified in a proband from the SAGE cohort in Stessman et al., 2017; although no specific phenotypic information for this proband is available, the primary diagnosis under which this cohort was broadly ascertained was developmental delay. Functional analysis of the ASD-associated p.Glu469Lys variant in transfected primary rat hippocampal neurons in Hlushchenko et al., 2018 (PMID 30123108) demonstrated that this variant enhanced SrGAP3 localization to dendritic spines and resulted in an increased density of inhibitory synapses in transfected hippocampal neurons compared to wild-type protein, with no other effects on dendritic spine density or morphology.

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

Two de novo missense variants in the SRGAP3 gene (one predicted to be probably damaging, the other predicted to be possibly damaging) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. A de novo missense variant that was predicted to be damaging was identified in a proband from the SAGE cohort in Stessman et al., 2017; although no specific phenotypic information for this proband is available, the primary diagnosis under which this cohort was broadly ascertained was developmental delay. Functional analysis of the ASD-associated p.Glu469Lys variant in transfected primary rat hippocampal neurons in Hlushchenko et al., 2018 (PMID 30123108) demonstrated that this variant enhanced SrGAP3 localization to dendritic spines and resulted in an increased density of inhibitory synapses in transfected hippocampal neurons compared to wild-type protein, with no other effects on dendritic spine density or morphology.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo missense variants in the SRGAP3 gene (one predicted to be probably damaging, the other predicted to be possibly damaging) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. A de novo missense variant that was predicted to be damaging was identified in a proband from the SAGE cohort in Stessman et al., 2017; although no specific phenotypic information for this proband is available, the primary diagnosis under which this cohort was broadly ascertained was developmental delay. Functional analysis of the ASD-associated p.Glu469Lys variant in transfected primary rat hippocampal neurons in Hlushchenko et al., 2018 (PMID 30123108) demonstrated that this variant enhanced SrGAP3 localization to dendritic spines and resulted in an increased density of inhibitory synapses in transfected hippocampal neurons compared to wild-type protein, with no other effects on dendritic spine density or morphology.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2018
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants in the SRGAP3 gene (one predicted to be probably damaging, the other predicted to be possibly damaging) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. A de novo missense variant that was predicted to be damaging was identified in a proband from the SAGE cohort in Stessman et al., 2017; although no specific phenotypic information for this proband is available, the primary diagnosis under which this cohort was broadly ascertained was developmental delay. Functional analysis of the ASD-associated p.Glu469Lys variant in transfected primary rat hippocampal neurons in Hlushchenko et al., 2018 (PMID 30123108) demonstrated that this variant enhanced SrGAP3 localization to dendritic spines and resulted in an increased density of inhibitory synapses in transfected hippocampal neurons compared to wild-type protein, with no other effects on dendritic spine density or morphology.

Reports Added
[ASD-Associated De Novo Mutations in Five Actin Regulators Show Both Shared and Distinct Defects in Dendritic Spines and Inhibitory Synapses in Cult...2018]
1/1/2017
icon
4

Increased from to 4

Description

Two de novo missense variants in the SRGAP3 gene (one predicted to be probably damaging, the other predicted to be possibly damaging) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014.

Krishnan Probability Score

Score 0.62135177026193

Ranking 82/25841 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 0.99999775022386

Ranking 353/18225 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 0.937

Ranking 97/239 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 0.42231376469318

Ranking 309/18665 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 0.42636103275081

Ranking 1162/20870 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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