rs140685

Variant names:

• chr15-26943312-C-T
• rs140685
• NM_000810.4:c.975C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000810.4(GABRA5):​c.975C>T​(p.Ala325Ala) 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:3
• Conservation: PhyloP100: -2.49
• Publications: 24 publications found

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]

GABRA5 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 79

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000810.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA5	NM_000810.4	MANE Select	c.975C>T	p.Ala325Ala	synonymous	Exon 10 of 11	NP_000801.1	P31644
	GABRA5	NM_001165037.2		c.975C>T	p.Ala325Ala	synonymous	Exon 10 of 11	NP_001158509.1	P31644

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA5	ENST00000335625.10	TSL:1 MANE Select	c.975C>T	p.Ala325Ala	synonymous	Exon 10 of 11	ENSP00000335592.5	P31644
	GABRA5	ENST00000355395.9	TSL:5	c.975C>T	p.Ala325Ala	synonymous	Exon 9 of 10	ENSP00000347557.5	P31644
	GABRA5	ENST00000400081.7	TSL:5	c.975C>T	p.Ala325Ala	synonymous	Exon 10 of 11	ENSP00000382953.3	P31644

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

GnomAD2 exomes AF: 0.462 AC: 95126 AN: 205864 AF XY: 0.459

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 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

African (AFR) AF: 0.521 AC: 17068 AN: 32752

American (AMR) AF: 0.517 AC: 20887 AN: 40386

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14371 AN: 25658

East Asian (EAS) AF: 0.328 AC: 12483 AN: 38116

South Asian (SAS) AF: 0.412 AC: 33723 AN: 81772

European-Finnish (FIN) AF: 0.418 AC: 21522 AN: 51478

Middle Eastern (MID) AF: 0.574 AC: 3303 AN: 5750

European-Non Finnish (NFE) AF: 0.454 AC: 498200 AN: 1097518

Other (OTH) AF: 0.467 AC: 27777 AN: 59478

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

African (AFR) AF: 0.520 AC: 21575 AN: 41498

American (AMR) AF: 0.510 AC: 7795 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 1956 AN: 3470

East Asian (EAS) AF: 0.330 AC: 1690 AN: 5126

South Asian (SAS) AF: 0.399 AC: 1923 AN: 4814

European-Finnish (FIN) AF: 0.408 AC: 4318 AN: 10584

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31697 AN: 67970

Other (OTH) AF: 0.493 AC: 1039 AN: 2108

Alfa AF: 0.473 Hom.: 34026

Bravo AF: 0.484

Asia WGS AF: 0.401 AC: 1393 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 79 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.7
DANN	Benign	0.89
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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