Human Gene Module / Chromosome 4 / GABRA4

GABRA4gamma-aminobutyric acid (GABA) A receptor, alpha 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 10
Rare Variants / Common Variants
7 / 7
Aliases
-
Associated Syndromes
-
Chromosome Band
4p12
Associated Disorders
-
Relevance to Autism

Studies have found genetic association between the GABRA4 gene and autism in the Caucasian and African-American populations.

Molecular Function

The encoded protein is a subunit of GABA-A receptor. Neurotransmission is predominantly mediated by a gated chloride channel activity intrinsic to the receptor.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GABRA4 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism Ma DQ , et al. (2005) Yes -
2 Recent Recommendation Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression Roberts DS , et al. (2005) No -
3 Positive Association Investigation of autism and GABA receptor subunit genes in multiple ethnic groups Collins AL , et al. (2006) Yes -
4 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy Klassen T , et al. (2011) No -
5 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
6 Support Transcriptomics of Gabra4 knockout mice reveals common NMDAR pathways underlying autism, memory, and epilepsy Fan C , et al. (2020) No -
7 Support - Vogel FD et al. (2022) No -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Samin A Sajan et al. () No ASD, ADHD, epilepsy/seizures
10 Highly Cited GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid Smith SS , et al. (1998) No -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1378C>T p.Arg460Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.634G>A p.Val212Ile missense_variant Unknown - - 38565639 Samin A Sajan et al. ()
c.899C>T p.Thr300Ile missense_variant De novo - - 38565639 Samin A Sajan et al. ()
c.899C>T p.Thr300Ile missense_variant De novo - Simplex 35152403 Vogel FD et al. (2022)
c.797C>T p.Pro266Leu missense_variant De novo - Simplex 38565639 Samin A Sajan et al. ()
c.1115A>C p.His372Pro missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1148A>G p.Asn383Ser missense_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
Common Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.722-186T>C;c.665-186T>C;c.664+2811T>C;c.692-186T>C - intron_variant - - - 16770606 Collins AL , et al. (2006)
c.875-327C>G;c.818-327C>G;c.665-327C>G;c.845-327C>G N/A intron_variant - - - 16770606 Collins AL , et al. (2006)
c.874+1091T>G;c.817+1091T>G;c.664+4240T>G;c.844+1091T>G - intron_variant - - - 16770606 Collins AL , et al. (2006)
c.1134+13106C>G;c.1077+13106C>G;c.924+13106C>G;c.1104+13106C>G - intron_variant - - - 16080114 Ma DQ , et al. (2005)
c.1135-9443A>T;c.1078-9443A>T;c.925-9443A>T;c.1105-9443A>T - intron_variant - - - 16770606 Collins AL , et al. (2006)
c.1134+13106C>G;c.1077+13106C>G;c.924+13106C>G;c.1104+13106C>G - intron_variant - - - 16770606 Collins AL , et al. (2006)
c.*574C>G N/A 3_prime_UTR_variant - - - 16770606 Collins AL , et al. (2006)
SFARI Gene score
2

Strong Candidate

Two gene-based studies have found association of a SNP within GABRA4 and autism. In one study (Ma et al., 2005), SNPS in a series of GABA receptor subunit genes were anlayized in 470 caucasian families. Significant allelic association was found for rs1912960 (p=0.01) in GABRA4. In the second study, another 557 Caucasian individuals and 54 Afircan-American individuals were analyzed for 35 SNPs in GABRB1 and GABRA4, with significant association at rs1912960 in the Caucasian sample (p=0.00073) and a different SNP in the African-American population.

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 gene-based studies have found association of a SNP within GABRA4 and autism. In one study (Ma et al., 2005), SNPS in a series of GABA receptor subunit genes were anlayized in 470 caucasian families. Significant allelic association was found for rs1912960 (p=0.01) in GABRA4. In the second study, another 557 Caucasian individuals and 54 Afircan-American individuals were analyzed for 35 SNPs in GABRB1 and GABRA4, with significant association at rs1912960 in the Caucasian sample (p=0.00073) and a different SNP in the African-American population.

1/1/2020
3
icon
3

Decreased from 3 to 3

Description

Two gene-based studies have found association of a SNP within GABRA4 and autism. In one study (Ma et al., 2005), SNPS in a series of GABA receptor subunit genes were anlayized in 470 caucasian families. Significant allelic association was found for rs1912960 (p=0.01) in GABRA4. In the second study, another 557 Caucasian individuals and 54 Afircan-American individuals were analyzed for 35 SNPs in GABRB1 and GABRA4, with significant association at rs1912960 in the Caucasian sample (p=0.00073) and a different SNP in the African-American population.

Reports Added
[Transcriptomics of Gabra4 knockout mice reveals common NMDAR pathways underlying autism, memory, and epilepsy.2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two gene-based studies have found association of a SNP within GABRA4 and autism. In one study (Ma et al., 2005), SNPS in a series of GABA receptor subunit genes were anlayized in 470 caucasian families. Significant allelic association was found for rs1912960 (p=0.01) in GABRA4. In the second study, another 557 Caucasian individuals and 54 Afircan-American individuals were analyzed for 35 SNPs in GABRB1 and GABRA4, with significant association at rs1912960 in the Caucasian sample (p=0.00073) and a different SNP in the African-American population.

Reports Added
[New Scoring Scheme]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Two gene-based studies have found association of a SNP within GABRA4 and autism. In one study (Ma et al., 2005), SNPS in a series of GABA receptor subunit genes were anlayized in 470 caucasian families. Significant allelic association was found for rs1912960 (p=0.01) in GABRA4. In the second study, another 557 Caucasian individuals and 54 Afircan-American individuals were analyzed for 35 SNPs in GABRB1 and GABRA4, with significant association at rs1912960 in the Caucasian sample (p=0.00073) and a different SNP in the African-American population.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Two gene-based studies have found association of a SNP within GABRA4 and autism. In one study (Ma et al., 2005), SNPS in a series of GABA receptor subunit genes were anlayized in 470 caucasian families. Significant allelic association was found for rs1912960 (p=0.01) in GABRA4. In the second study, another 557 Caucasian individuals and 54 Afircan-American individuals were analyzed for 35 SNPs in GABRB1 and GABRA4, with significant association at rs1912960 in the Caucasian sample (p=0.00073) and a different SNP in the African-American population.

Krishnan Probability Score

Score 0.6037564316021

Ranking 360/25841 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 0.98141656865906

Ranking 2091/18225 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 0.87496862655523

Ranking 4558/18665 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 14

Ranking 138/461 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 0.30452427106896

Ranking 2667/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
GABRG3 gamma-aminobutyric acid (GABA) A receptor, gamma 3 Rat Protein Binding 79211 P28473
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