rs140681

Positions:

• chr15-26937065-G-A

Variant summary

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

The NM_000810.4(GABRA5):​c.581-120G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.094 in 1,267,082 control chromosomes in the GnomAD database, including 6,717 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 0.095 (793 hom., cov: 33)
  • Exomes 𝑓: 0.094 (5924 hom.)
• Consequence: GABRA5 NM_000810.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04

Genes affected

GABRA5 (HGNC:4079): (gamma-aminobutyric acid type A receptor subunit alpha5) 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. Transcript variants utilizing three different alternative non-coding first exons have been described. [provided by RefSeq, Jul 2008]

GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA5	NM_000810.4	c.581-120G>A		intron_variant		ENST00000335625.10	NP_000801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA5	ENST00000335625.10	c.581-120G>A		intron_variant		1	NM_000810.4	ENSP00000335592	P1

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 14405 AN: 152092 Hom.: 790 Cov.: 33

Gnomad AFR AF: 0.0987

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0779

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0818

Gnomad OTH AF: 0.0913

GnomAD4 exome AF: 0.0939 AC: 104661 AN: 1114872 Hom.: 5924 AF XY: 0.0983 AC XY: 56081 AN XY: 570570

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.0870

Gnomad4 ASJ exome AF: 0.0667

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0798

Gnomad4 OTH exome AF: 0.0927

GnomAD4 genome AF: 0.0947 AC: 14420 AN: 152210 Hom.: 793 Cov.: 33 AF XY: 0.0992 AC XY: 7380 AN XY: 74410

Gnomad4 AFR AF: 0.0987

Gnomad4 AMR AF: 0.0780

Gnomad4 ASJ AF: 0.0611

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0818

Gnomad4 OTH AF: 0.0894

Alfa AF: 0.0878 Hom.: 164

Bravo AF: 0.0914

Asia WGS AF: 0.182 AC: 634 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.38
DANN	Benign	0.51

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: rs140681; hg19: chr15-27182212;