rs13151759

Variant names:

• chr4-46993636-G-T
• rs13151759
• NM_000809.4:c.-212C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000809.4(GABRA4):​c.-212C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 574,154 control chromosomes in the GnomAD database, including 32,591 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (8769 hom., cov: 32)
  • Exomes 𝑓: 0.33 (23822 hom.)
• Consequence: GABRA4 NM_000809.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10

Genes affected

GABRA4 (HGNC:4078): (gamma-aminobutyric acid type A receptor subunit alpha4) 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]

GABRB1 (HGNC:4081): (gamma-aminobutyric acid type A receptor subunit beta1) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.-212C>A		upstream_gene_variant		ENST00000264318.4	NP_000800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.-212C>A		upstream_gene_variant		1	NM_000809.4	ENSP00000264318.3

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50969 AN: 151730 Hom.: 8746 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.349

GnomAD4 exome AF: 0.330 AC: 139379 AN: 422306 Hom.: 23822 Cov.: 4 AF XY: 0.324 AC XY: 72419 AN XY: 223734

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.391

Gnomad4 EAS exome AF: 0.324

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.359

Gnomad4 OTH exome AF: 0.341

GnomAD4 genome AF: 0.336 AC: 51036 AN: 151848 Hom.: 8769 Cov.: 32 AF XY: 0.325 AC XY: 24087 AN XY: 74196

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.390

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.359

Gnomad4 OTH AF: 0.351

Alfa AF: 0.360 Hom.: 8630

Bravo AF: 0.351

Asia WGS AF: 0.268 AC: 930 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs13151759; hg19: chr4-46995653;