Human Gene Module / Chromosome 8 / ARHGEF10

ARHGEF10Rho guanine nucleotide exchange factor 10

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
13 / 2
Aliases
ARHGEF10, GEF10,  SNCV
Associated Syndromes
-
Chromosome Band
8p23.3
Associated Disorders
-
Relevance to Autism

Arhgef10 knockout mice were found to exhibit reduced social interaction, hyperactivity, decreased depression-like and anxiety-like behavior, increased levels of neurotransmitters including serotonin, norepinephrine, and dopamine in different brain regions, and decreased levels of monoamine oxidase A (MAO-A) in several brain regions (Lu et al., 2018). De novo and inherited missense variants in ARHGEF10 have also been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

Molecular Function

This gene encodes a Rho guanine nucleotide exchange factor (GEF). Rho GEFs regulate the activity of small Rho GTPases by stimulating the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and may play a role in neural morphogenesis. Mutations in this gene are associated with slowed nerve conduction velocity (SNCV).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ARHGEF10 (8 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 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
3 Primary Impairment of social behaviors in Arhgef10 knockout mice Lu DH , et al. (2018) No -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support - Catusi I et al. (2021) No -
6 Support - Zhou X et al. (2022) Yes -
7 Positive Association - Yi Yang et al. () Yes -
8 Support - Ashlesha Gogate et al. (2024) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 33925474 Catusi I et al. (2021)
c.266-4C>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.607A>G p.Thr203Ala missense_variant Familial - - 28831199 Li J , et al. (2017)
c.643G>C p.Asp215His missense_variant Familial - - 28831199 Li J , et al. (2017)
c.3034G>A p.Ala1012Thr missense_variant De novo - - 28831199 Li J , et al. (2017)
c.2475G>A p.Thr825= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3335C>T p.Ser1112Phe missense_variant Familial - - 28831199 Li J , et al. (2017)
c.3423C>T p.His1141= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.53A>G p.Tyr18Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.898C>T p.Arg300Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.531C>T p.Cys177= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.193+2T>C - splice_site_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1630C>G p.Gln544Glu missense_variant Unknown Not maternal Simplex 39632905 Ashlesha Gogate et al. (2024)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intron_variant - - - 38821058 Yi Yang et al. ()
Unnamed: 5 Unnamed: 6 intron_variant - - - 38821058 Yi Yang et al. ()
SFARI Gene score
2

Strong Candidate

Arhgef10 knockout mice were found to exhibit reduced social interaction, hyperactivity, decreased depression-like and anxiety-like behavior, increased levels of neurotransmitters including serotonin, norepinephrine, and dopamine in different brain regions, and decreased levels of monoamine oxidase A (MAO-A) in several brain regions (Lu et al., 2018). De novo and inherited missense variants in ARHGEF10 have also been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

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

Arhgef10 knockout mice were found to exhibit reduced social interaction, hyperactivity, decreased depression-like and anxiety-like behavior, increased levels of neurotransmitters including serotonin, norepinephrine, and dopamine in different brain regions, and decreased levels of monoamine oxidase A (MAO-A) in several brain regions (Lu et al., 2018). De novo and inherited missense variants in ARHGEF10 have also been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

4/1/2021
3
icon
3

Decreased from 3 to 3

Description

Arhgef10 knockout mice were found to exhibit reduced social interaction, hyperactivity, decreased depression-like and anxiety-like behavior, increased levels of neurotransmitters including serotonin, norepinephrine, and dopamine in different brain regions, and decreased levels of monoamine oxidase A (MAO-A) in several brain regions (Lu et al., 2018). De novo and inherited missense variants in ARHGEF10 have also been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

Reports Added
[8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Arhgef10 knockout mice were found to exhibit reduced social interaction, hyperactivity, decreased depression-like and anxiety-like behavior, increased levels of neurotransmitters including serotonin, norepinephrine, and dopamine in different brain regions, and decreased levels of monoamine oxidase A (MAO-A) in several brain regions (Lu et al., 2018). De novo and inherited missense variants in ARHGEF10 have also been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

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

Decreased from 4 to 4

Description

Arhgef10 knockout mice were found to exhibit reduced social interaction, hyperactivity, decreased depression-like and anxiety-like behavior, increased levels of neurotransmitters including serotonin, norepinephrine, and dopamine in different brain regions, and decreased levels of monoamine oxidase A (MAO-A) in several brain regions (Lu et al., 2018). De novo and inherited missense variants in ARHGEF10 have also been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2018
icon
4

Increased from to 4

Description

Arhgef10 knockout mice were found to exhibit reduced social interaction, hyperactivity, decreased depression-like and anxiety-like behavior, increased levels of neurotransmitters including serotonin, norepinephrine, and dopamine in different brain regions, and decreased levels of monoamine oxidase A (MAO-A) in several brain regions (Lu et al., 2018). De novo and inherited missense variants in ARHGEF10 have also been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

Krishnan Probability Score

Score 0.4473715516038

Ranking 12556/25841 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 1.1080474135153E-13

Ranking 17496/18225 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 0.94846829238294

Ranking 17696/18665 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 -0.12300801310245

Ranking 13240/20870 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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