Human Gene Module / Chromosome 7 / RAC1

RAC1Rac family small GTPase 1

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 10
Rare Variants / Common Variants
17 / 0
Aliases
RAC1, MIG5,  Rac-1,  TC-25,  p21-Rac1
Associated Syndromes
-
Chromosome Band
7p22.1
Associated Disorders
ASD
Relevance to Autism

Viral expression of a dominant-negative form of Rac1 following bilateral injection into the prelimbic regions of wild-type mice resulted in ASD-like social deficits and reduced NMDAR-ESPC in PFC pyramidal neurons; conversely, viral expression of constitutively active Rac1 in SHANK3-deficient mice rescued ASD-like social deficits and NMDAR hypofunction (Duffney et al., 2015). De novo ASD-associated missense variants in the TRIO gene were experimentally shown to affect Rac1 activiation in two studies (Sadybekov et al., 2017; Katrancha et al., 2017). De novo missense variants in the RAC1 gene were identified in seven individuals presenting with intellectual disability and brain malformations; two of these individuals presented with stereotypic movements, and one was diagnosed with autism (Reijnders et al., 2017). Ma et al., 2022 recently demonstrated that bidirectional dysregulation of Rac1 activity in the medial prefrontal cortex (mPFC) dictated shared social deficits in mice.

Molecular Function

The protein encoded by this gene is a GTPase which belongs to the RAS superfamily of small GTP-binding proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to RAC1 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators Duffney LJ , et al. (2015) No -
2 Recent Recommendation RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes Reijnders MRF , et al. (2017) No ASD, stereotypic movements
3 Support An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio Sadybekov A , et al. (2017) No -
4 Support Neurodevelopmental disease-associated de novo mutations and rare sequence variants affect TRIO GDP/GTP exchange factor activity Katrancha SM , et al. (2017) No -
5 Support An Intellectual Disability-Related Missense Mutation in Rac1 Prevents LTP Induction Tian C , et al. (2018) No -
6 Support - Banka S et al. (2022) No Autistic features, stereotypy, ADHD
7 Support - Zhou X et al. (2022) Yes -
8 Recent Recommendation - Ma B et al. (2022) Yes -
9 Support - Spataro N et al. (2023) Yes Learning disability
10 Support - Priolo M et al. (2023) No -
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.181C>G p.Gln61Glu missense_variant De novo - - 35139179 Banka S et al. (2022)
c.190T>G p.Tyr64Asp missense_variant De novo - - 35139179 Banka S et al. (2022)
c.190T>G p.Tyr64Asp missense_variant Unknown - - 35139179 Banka S et al. (2022)
c.191A>G p.Tyr64Cys missense_variant De novo - - 35139179 Banka S et al. (2022)
c.202C>A p.Arg68Ser missense_variant Unknown - - 35139179 Banka S et al. (2022)
c.218C>T p.Pro73Leu missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.53G>A p.Cys18Tyr missense_variant De novo - - 28886345 Reijnders MRF , et al. (2017)
c.116A>G p.Asn39Ser missense_variant De novo - - 28886345 Reijnders MRF , et al. (2017)
c.151G>A p.Val51Met missense_variant De novo - - 28886345 Reijnders MRF , et al. (2017)
c.151G>C p.Val51Leu missense_variant De novo - - 28886345 Reijnders MRF , et al. (2017)
c.190T>G p.Tyr64Asp missense_variant De novo - - 28886345 Reijnders MRF , et al. (2017)
c.218C>T p.Pro73Leu missense_variant De novo - - 28886345 Reijnders MRF , et al. (2017)
c.126C>T p.Ala42%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.184G>A p.Glu62Lys missense_variant De novo - Simplex 37059841 Priolo M et al. (2023)
c.470G>A p.Cys157Tyr missense_variant De novo - - 28886345 Reijnders MRF , et al. (2017)
c.475G>A p.Ala159Thr missense_variant De novo - Simplex 37059841 Priolo M et al. (2023)
c.202C>G p.Arg68Gly missense_variant Unknown Not maternal - 35139179 Banka S et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Viral expression of a dominant-negative form of Rac1 following bilateral injection into the prelimbic regions of wild-type mice resulted in ASD-like social deficits and reduced NMDAR-ESPC in PFC pyramidal neurons; conversely, viral expression of constitutively active Rac1 in SHANK3-deficient mice rescued ASD-like social deficits and NMDAR hypofunction (Duffney et al., 2015). De novo ASD-associated missense variants in the TRIO gene were experimentally shown to affect Rac1 activiation in two studies (Sadybekov et al., 2017; Katrancha et al., 2017). De novo missense variants in the RAC1 gene were identified in seven individuals presenting with intellectual disability and brain malformations; two of these individuals presented with stereotypic movements, and one was diagnosed with autism (Reijnders et al., 2017).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Viral expression of a dominant-negative form of Rac1 following bilateral injection into the prelimbic regions of wild-type mice resulted in ASD-like social deficits and reduced NMDAR-ESPC in PFC pyramidal neurons; conversely, viral expression of constitutively active Rac1 in SHANK3-deficient mice rescued ASD-like social deficits and NMDAR hypofunction (Duffney et al., 2015). De novo ASD-associated missense variants in the TRIO gene were experimentally shown to affect Rac1 activiation in two studies (Sadybekov et al., 2017; Katrancha et al., 2017). De novo missense variants in the RAC1 gene were identified in seven individuals presenting with intellectual disability and brain malformations; two of these individuals presented with stereotypic movements, and one was diagnosed with autism (Reijnders et al., 2017).

Reports Added
[New Scoring Scheme]
7/1/2019
5
icon
S

Decreased from 5 to S

Description

Viral expression of a dominant-negative form of Rac1 following bilateral injection into the prelimbic regions of wild-type mice resulted in ASD-like social deficits and reduced NMDAR-ESPC in PFC pyramidal neurons; conversely, viral expression of constitutively active Rac1 in SHANK3-deficient mice rescued ASD-like social deficits and NMDAR hypofunction (Duffney et al., 2015). De novo ASD-associated missense variants in the TRIO gene were experimentally shown to affect Rac1 activiation in two studies (Sadybekov et al., 2017; Katrancha et al., 2017). De novo missense variants in the RAC1 gene were identified in seven individuals presenting with intellectual disability and brain malformations; two of these individuals presented with stereotypic movements, and one was diagnosed with autism (Reijnders et al., 2017).

7/1/2018
5
icon
5

Decreased from 5 to 5

Description

Viral expression of a dominant-negative form of Rac1 following bilateral injection into the prelimbic regions of wild-type mice resulted in ASD-like social deficits and reduced NMDAR-ESPC in PFC pyramidal neurons; conversely, viral expression of constitutively active Rac1 in SHANK3-deficient mice rescued ASD-like social deficits and NMDAR hypofunction (Duffney et al., 2015). De novo ASD-associated missense variants in the TRIO gene were experimentally shown to affect Rac1 activiation in two studies (Sadybekov et al., 2017; Katrancha et al., 2017). De novo missense variants in the RAC1 gene were identified in seven individuals presenting with intellectual disability and brain malformations; two of these individuals presented with stereotypic movements, and one was diagnosed with autism (Reijnders et al., 2017).

Reports Added
[An Intellectual Disability-Related Missense Mutation in Rac1 Prevents LTP Induction.2018]
10/1/2017
icon
5

Increased from to 5

Description

Viral expression of a dominant-negative form of Rac1 following bilateral injection into the prelimbic regions of wild-type mice resulted in ASD-like social deficits and reduced NMDAR-ESPC in PFC pyramidal neurons; conversely, viral expression of constitutively active Rac1 in SHANK3-deficient mice rescued ASD-like social deficits and NMDAR hypofunction (Duffney et al., 2015). De novo ASD-associated missense variants in the TRIO gene were experimentally shown to affect Rac1 activiation in two studies (Sadybekov et al., 2017; Katrancha et al., 2017). De novo missense variants in the RAC1 gene were identified in seven individuals presenting with intellectual disability and brain malformations; two of these individuals presented with stereotypic movements, and one was diagnosed with autism (Reijnders et al., 2017).

Krishnan Probability Score

Score 0.56887306472334

Ranking 1087/25841 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 0.57239505272813

Ranking 5126/18225 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 0.87693811435697

Ranking 4666/18665 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 0.11739909768326

Ranking 5773/20870 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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