chr15-26937065-G-A

Variant names:

• chr15-26937065-G-A
• rs140681
• NM_000810.4:c.581-120G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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]

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]

GABRB3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 43

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epilepsy, childhood absence, susceptibility to, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GABRA5	NM_000810.4	c.581-120G>A		intron_variant	Intron 7 of 10	ENST00000335625.10	NP_000801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA5	ENST00000335625.10	c.581-120G>A		intron_variant	Intron 7 of 10	1	NM_000810.4	ENSP00000335592.5

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

African (AFR) AF: 0.104 AC: 2727 AN: 26248

American (AMR) AF: 0.0870 AC: 3749 AN: 43086

Ashkenazi Jewish (ASJ) AF: 0.0667 AC: 1560 AN: 23374

East Asian (EAS) AF: 0.140 AC: 5300 AN: 37780

South Asian (SAS) AF: 0.217 AC: 16721 AN: 77226

European-Finnish (FIN) AF: 0.110 AC: 5259 AN: 47892

Middle Eastern (MID) AF: 0.115 AC: 595 AN: 5158

European-Non Finnish (NFE) AF: 0.0798 AC: 64237 AN: 805430

Other (OTH) AF: 0.0927 AC: 4513 AN: 48678

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

African (AFR) AF: 0.0987 AC: 4100 AN: 41532

American (AMR) AF: 0.0780 AC: 1193 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3472

East Asian (EAS) AF: 0.151 AC: 779 AN: 5166

South Asian (SAS) AF: 0.229 AC: 1102 AN: 4818

European-Finnish (FIN) AF: 0.110 AC: 1169 AN: 10610

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0818 AC: 5560 AN: 67992

Other (OTH) AF: 0.0894 AC: 189 AN: 2114

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
PhyloP100		-1.0
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: rs140681; hg19: chr15-27182212;