GABRA4

protein-coding

gamma-aminobutyric acid type A receptor subunit alpha4, the group of Gamma-aminobutyric acid type A receptor subunits

Gene summary

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. This gene encodes subunit alpha-4, which is involved in the etiology of autism and eventually increases autism risk through interaction with another subunit, gamma-aminobutyric acid receptor beta-1 (GABRB1). Alternatively spliced transcript variants encoding different isoforms have been found in this gene.[provided by RefSeq, Feb 2011]

MANE transcript

NM_000809.4

Inheritance

ClinVar variants

P:1U:58B:12

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr4:46,918,900-46,993,581

External References & Databases

Ensembl (ENSG00000109158)

Transcript & Mutation Effects

hg38 • Region Span ~74.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: G2P

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

genetic developmental and epileptic encephalopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Ambry Genetics

genetic developmental and epileptic encephalopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Illumina

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GABRA4 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 45

not providedTotal: 24

GABRA4-related Epileptic and Neurodevelopmental DisorderTotal: 1

GABRA4-related developmental and epileptic encephalopathyTotal: 1

GABRA4-associated disorderTotal: 1

GABRA4-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000809.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	3 clinvar	2 clinvar	6
missense		1 clinvar	55 clinvar	6 clinvar	1 clinvar	63
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	58	9	3	71

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000809.4	RefSeq	NP_000800.2	9	MANE Select
ENST00000264318.4	Ensembl	ENSP00000264318.3	9	MANE Select
NM_001204266.2	RefSeq	NP_001191195.1	9	Standard
NM_001204267.2	RefSeq	NP_001191196.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Retrograde endocannabinoid signaling - Homo sapiens (human)
GABAergic synapse - Homo sapiens (human)
Nicotine addiction - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Taste transduction - Homo sapiens (human)

Biological Process

signal transduction
gamma-aminobutyric acid signaling pathway
chemical synaptic transmission
central nervous system development
ion transmembrane transport

Molecular Function

GABA-A receptor activity
extracellular ligand-gated ion channel activity
inhibitory extracellular ligand-gated ion channel activity
chloride channel activity
benzodiazepine receptor activity

Cellular Component

plasma membrane
integral component of plasma membrane
cell junction
dendrite membrane
chloride channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264318
Coding exons: 9
Length: 75508
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125746
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.00	208	307	0.678	0.0000156	3608
Missense (PolyPhen)		62	156.91	0.39513		1901
Synonymous	-1.64	134	112	1.20	0.00000607	1108
Loss of Function	3.62	4	22.6	0.177	0.00000119	293

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00013	0.000088	rare
South Asian	0.000038	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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.;

Recessive Scores

pRec: 0.134

Intolerance Scores

LoFtool: 0.0240
RVIS EVS: 0.26
RVIS percentile EVS: 70.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.881

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium