Human Gene Module / Chromosome X / GABRA3

GABRA3Gamma-aminobutyric acid (GABA) A receptor, alpha 3

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
1 / 3
Rare Variants / Common Variants
8 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xq28
Associated Disorders
DD/NDD, ID
Relevance to Autism

A maternally-inherited missense variant in GABRA3 that resulted in skipping of exon 2 of the gene was detected in a male ASD patient (Piton et al., 2012).

Molecular Function

Subunit of the GABA receptor. GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.

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Reports related to GABRA3 (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals Piton A , et al. (2012) Yes -
2 Recent Recommendation Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features Niturad CE , et al. (2017) No DD, ID
3 Support De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy Butler KM , et al. (2018) No DD
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Familial Maternal - 29053855 Niturad CE , et al. (2017)
c.*154A>G - missense_variant De novo - Simplex 29053855 Niturad CE , et al. (2017)
c.902C>T p.Pro301Leu missense_variant Unknown - - 29961870 Butler KM , et al. (2018)
c.34A>T p.Thr12Ser splice_site_variant Familial Maternal - 23169495 Piton A , et al. (2012)
c.139G>A p.Gly47Arg missense_variant Familial Maternal Multiplex 29053855 Niturad CE , et al. (2017)
c.1219C>T p.Leu407= missense_variant Familial Maternal Multi-generational 29053855 Niturad CE , et al. (2017)
c.497C>T p.Thr166Met missense_variant Familial Maternal Multi-generational 29053855 Niturad CE , et al. (2017)
c.725A>T p.Gln242Leu missense_variant Familial Maternal Multi-generational 29053855 Niturad CE , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A maternally-inherited missense variant in GABRA3 that resulted in skipping of exon 2 of the gene was detected in a male ASD patient (Piton et al., 2012). Niturad et al., 2017 reported seven individuals with GABRA3 variants that presented with a range of epileptic seizure types and varying degrees of developmental delay and/or intellectual disability; one of these individuals presented with autism spectrum disorder, while another presented with autistic behavior.

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

A maternally-inherited missense variant in GABRA3 that resulted in skipping of exon 2 of the gene was detected in a male ASD patient (Piton et al., 2012). Niturad et al., 2017 reported seven individuals with GABRA3 variants that presented with a range of epileptic seizure types and varying degrees of developmental delay and/or intellectual disability; one of these individuals presented with autism spectrum disorder, while another presented with autistic behavior.

Reports Added
[New Scoring Scheme]
7/1/2018
icon
S

Score remained at S

Description

A maternally-inherited missense variant in GABRA3 that resulted in skipping of exon 2 of the gene was detected in a male ASD patient (Piton et al., 2012). Niturad et al., 2017 reported seven individuals with GABRA3 variants that presented with a range of epileptic seizure types and varying degrees of developmental delay and/or intellectual disability; one of these individuals presented with autism spectrum disorder, while another presented with autistic behavior.

Reports Added
[De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy.2018]
Krishnan Probability Score

Score 0.50580479450918

Ranking 1898/25841 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 0.27321394581542

Ranking 6623/18225 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 0.85880617320383

Ranking 3799/18665 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
Larsen Cumulative Evidence Score

Score 2

Ranking 385/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.18194376445652

Ranking 4564/20870 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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