Human Gene Module / Chromosome 14 / ARHGAP5

ARHGAP5Rho GTPase activating protein 5

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
10 / 0
Aliases
ARHGAP5, GFI2,  RhoGAP5,  p190-B,  p190BRhoGAP
Associated Syndromes
-
Chromosome Band
14q12
Associated Disorders
-
Relevance to Autism

Two de novo variants in the ARHGAP5 gene (one loss-of-function variant, one missense variant predicted in silico to be damaging) were identified in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified ARHGAP5 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Molecular Function

Rho GTPase activating protein 5 negatively regulates RHO GTPases, a family which may mediate cytoskeleton changes by stimulating the hydrolysis of bound GTP.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ARHGAP5 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
4 Support De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis Wang S , et al. (2018) No -
5 Support - Alonso-Gonzalez A et al. (2021) Yes -
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3865+5G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.85A>G p.Asn29Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1717G>A p.Ala573Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1748G>A p.Arg583His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2482C>T p.Arg828Ter stop_gained De novo - Multiplex 30257206 Wang S , et al. (2018)
c.983A>C p.Gln328Pro missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1462G>T p.Glu488Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2101G>C p.Ala701Pro missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1441G>T p.Glu481Ter stop_gained De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.3559_3562del p.Lys1187GlufsTer35 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo variants in the ARHGAP5 gene (one loss-of-function variant, one missense variant predicted in silico to be damaging) were identified in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified ARHGAP5 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

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 variants in the ARHGAP5 gene (one loss-of-function variant, one missense variant predicted in silico to be damaging) were identified in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified ARHGAP5 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Two de novo variants in the ARHGAP5 gene (one loss-of-function variant, one missense variant predicted in silico to be damaging) were identified in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified ARHGAP5 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo variants in the ARHGAP5 gene (one loss-of-function variant, one missense variant predicted in silico to be damaging) were identified in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified ARHGAP5 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Reports Added
[New Scoring Scheme]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Two de novo variants in the ARHGAP5 gene (one loss-of-function variant, one missense variant predicted in silico to be damaging) were identified in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified ARHGAP5 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Reports Added
[De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.2018]
7/1/2018
icon
4

Increased from to 4

Description

Two de novo variants in the ARHGAP5 gene (one loss-of-function variant, one missense variant predicted in silico to be damaging) were identified in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified ARHGAP5 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Krishnan Probability Score

Score 0.56822658606677

Ranking 1129/25841 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 0.98705369807694

Ranking 1924/18225 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 0.945

Ranking 88/239 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 0.14357136224992

Ranking 83/18665 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 0.10426978149612

Ranking 6039/20870 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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