rs2055943

chr4-46965262-C-A

Variant summary

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

The NM_000809.4(GABRA4):c.875-33G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,369,300 control chromosomes in the GnomAD database, including 49,018 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 0.23 (4358 hom., cov: 32)
  • Exomes 𝑓: 0.27 (44660 hom.)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.607

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA4	NM_000809.4	c.875-33G>T		intron_variant		ENST00000264318.4
GABRA4	NM_001204266.2	c.818-33G>T		intron_variant
GABRA4	NM_001204267.2	c.665-33G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA4	ENST00000264318.4	c.875-33G>T		intron_variant		1	NM_000809.4	P1
GABRA4	ENST00000508560.5	c.*696-33G>T		intron_variant, NMD_transcript_variant		3
GABRA4	ENST00000511523.5	c.*543-33G>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35414 AN: 151416 Hom.: 4357 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.247

GnomAD3 exomes AF: 0.238 AC: 32519 AN: 136656 Hom.: 4131 AF XY: 0.241 AC XY: 17605 AN XY: 72982

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.349

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.267 AC: 324748 AN: 1217766 Hom.: 44660 Cov.: 28 AF XY: 0.265 AC XY: 156051 AN XY: 589614

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.311

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.181

Gnomad4 NFE exome AF: 0.278

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.234 AC: 35427 AN: 151534 Hom.: 4358 Cov.: 32 AF XY: 0.226 AC XY: 16744 AN XY: 73986

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.246

Alfa AF: 0.266 Hom.: 5212

Bravo AF: 0.235

Asia WGS AF: 0.213 AC: 739 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.35
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2055943; hg19: chr4-46967279; COSMIC: COSV51928439;