rs140685

chr15-26943312-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000810.4(GABRA5):c.975C>T(p.Ala325=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,584,982 control chromosomes in the GnomAD database, including 166,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17527 hom., cov: 33)
  • Exomes 𝑓: 0.45 (148566 hom.)
• Consequence: GABRA5 NM_000810.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.49

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 15-26943312-C-T is Benign according to our data. Variant chr15-26943312-C-T is described in ClinVar as [Benign]. Clinvar id is 1252856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA5	NM_000810.4	c.975C>T	p.Ala325=	synonymous_variant	10/11	ENST00000335625.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA5	ENST00000335625.10	c.975C>T	p.Ala325=	synonymous_variant	10/11	1	NM_000810.4	P1
GABRA5	ENST00000355395.9	c.975C>T	p.Ala325=	synonymous_variant	9/10	5		P1
GABRA5	ENST00000400081.7	c.975C>T	p.Ala325=	synonymous_variant	10/11	5		P1

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72444 AN: 151956 Hom.: 17510 Cov.: 33

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.489

GnomAD3 exomes AF: 0.462 AC: 95126 AN: 205864 Hom.: 22365 AF XY: 0.459 AC XY: 50709 AN XY: 110518

Gnomad AFR exome AF: 0.527

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.560

Gnomad EAS exome AF: 0.342

Gnomad SAS exome AF: 0.411

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.453 AC: 649334 AN: 1432908 Hom.: 148566 Cov.: 45 AF XY: 0.452 AC XY: 320930 AN XY: 710016

Gnomad4 AFR exome AF: 0.521

Gnomad4 AMR exome AF: 0.517

Gnomad4 ASJ exome AF: 0.560

Gnomad4 EAS exome AF: 0.328

Gnomad4 SAS exome AF: 0.412

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.467

GnomAD4 genome AF: 0.477 AC: 72505 AN: 152074 Hom.: 17527 Cov.: 33 AF XY: 0.474 AC XY: 35263 AN XY: 74348

Gnomad4 AFR AF: 0.520

Gnomad4 AMR AF: 0.510

Gnomad4 ASJ AF: 0.564

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.399

Gnomad4 FIN AF: 0.408

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.493

Alfa AF: 0.472 Hom.: 27922

Bravo AF: 0.484

Asia WGS AF: 0.401 AC: 1393 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2019

- -

Developmental and epileptic encephalopathy, 79 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	6.7
Dann	Benign	0.89

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: rs140685; hg19: chr15-27188459; COSMIC: COSV59476262; COSMIC: COSV59476262;