15-26883351-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000810.4(GABRA5):c.291C>T(p.Asp97=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000669 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: GABRA5 NM_000810.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.884

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 15-26883351-C-T is Benign according to our data. Variant chr15-26883351-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 713019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.884 with no splicing effect.
• BS2: High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA5	NM_000810.4	c.291C>T	p.Asp97=	synonymous_variant	6/11	ENST00000335625.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA5	ENST00000335625.10	c.291C>T	p.Asp97=	synonymous_variant	6/11	1	NM_000810.4	P1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000534 AC: 133 AN: 249268 Hom.: 0 AF XY: 0.000577 AC XY: 78 AN XY: 135234

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000646

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000680 AC: 994 AN: 1461660 Hom.: 0 Cov.: 35 AF XY: 0.000671 AC XY: 488 AN XY: 727126

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000709

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74478

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000703 Hom.: 0

Bravo AF: 0.000495

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GABRA5: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	9.0
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs79274924; hg19: chr15-27128498; COSMIC: COSV100164977; COSMIC: COSV100164977;