Human Gene Module / Chromosome 7 / RAC1

RAC1Rac family small GTPase 1

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
0 / 5
Rare Variants / Common Variants
7 / 0
Aliases
RAC1, MIG5,  Rac-1,  TC-25,  p21-Rac1
Associated Syndromes
-
Genetic Category
Syndromic, Functional
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).

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.

Reports related to RAC1 (5 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 -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.53G>A p.Cys18Tyr missense_variant De novo NA - 28886345 Reijnders MRF , et al. (2017)
c.116A>G p.Asn39Ser missense_variant De novo NA - 28886345 Reijnders MRF , et al. (2017)
c.151G>A p.Val51Met missense_variant De novo NA - 28886345 Reijnders MRF , et al. (2017)
c.151G>C p.Val51Leu missense_variant De novo NA - 28886345 Reijnders MRF , et al. (2017)
c.190T>G p.Tyr64Asp missense_variant De novo NA - 28886345 Reijnders MRF , et al. (2017)
c.218C>T p.Pro73Leu missense_variant De novo NA - 28886345 Reijnders MRF , et al. (2017)
c.470G>A p.Cys157Tyr missense_variant De novo NA - 28886345 Reijnders MRF , et al. (2017)
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

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
5.1
icon
5

Decreased from 5.1 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).

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.
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
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).
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.
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