NM_000810.4:c.498-4877A>G

Variant names:

• chr15-26909926-A-G
• rs4073083
• NM_000810.4:c.498-4877A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000810.4(GABRA5):​c.498-4877A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 152,260 control chromosomes in the GnomAD database, including 61,687 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 0.90 (61687 hom., cov: 34)
• Consequence: GABRA5 NM_000810.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.178
• Publications: 2 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA5	NM_000810.4	c.498-4877A>G		intron_variant	Intron 6 of 10	ENST00000335625.10	NP_000801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA5	ENST00000335625.10	c.498-4877A>G		intron_variant	Intron 6 of 10	1	NM_000810.4	ENSP00000335592.5

Frequencies

GnomAD3 genomes AF: 0.899 AC: 136799 AN: 152142 Hom.: 61653 Cov.: 34

Gnomad AFR AF: 0.921

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.912

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.904

Gnomad OTH AF: 0.906

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.899 AC: 136886 AN: 152260 Hom.: 61687 Cov.: 34 AF XY: 0.896 AC XY: 66721 AN XY: 74444

African (AFR) AF: 0.921 AC: 38264 AN: 41550

American (AMR) AF: 0.841 AC: 12872 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.948 AC: 3290 AN: 3472

East Asian (EAS) AF: 0.870 AC: 4485 AN: 5154

South Asian (SAS) AF: 0.833 AC: 4023 AN: 4828

European-Finnish (FIN) AF: 0.912 AC: 9678 AN: 10614

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.904 AC: 61488 AN: 68024

Other (OTH) AF: 0.901 AC: 1903 AN: 2112

Alfa AF: 0.900 Hom.: 19023

Bravo AF: 0.896

Asia WGS AF: 0.848 AC: 2952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.37
PhyloP100		-0.18
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: rs4073083; hg19: chr15-27155073;