chr15-26869279-A-G

Position:

• chr15-26869279-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000810.4(GABRA5):​c.31A>G​(p.Met11Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,948 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 Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GABRA5 NM_000810.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.55

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]

GABRA5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRA5. . Gene score misZ 3.2308 (greater than the threshold 3.09). Trascript score misZ 3.2557 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 79.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41340992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA5	NM_000810.4	c.31A>G	p.Met11Val	missense_variant	3/11	ENST00000335625.10	NP_000801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA5	ENST00000335625.10	c.31A>G	p.Met11Val	missense_variant	3/11	1	NM_000810.4	ENSP00000335592.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455948 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 724884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

GABRA5-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2023

The GABRA5 c.31A>G variant is predicted to result in the amino acid substitution p.Met11Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;T;.;.;.;.
Eigen	Benign	-0.082
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	.;.;T;T;T;.;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N;N;N;.;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.81	N;N;N;N;N;D;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0090	D;D;D;D;D;.;D
Sift4G	Uncertain	0.041	D;D;D;T;T;.;T
Polyphen		0.0010	B;B;B;.;.;.;.
Vest4		0.67
MutPred		0.54		Gain of catalytic residue at M11 (P = 0.0055);Gain of catalytic residue at M11 (P = 0.0055);Gain of catalytic residue at M11 (P = 0.0055);Gain of catalytic residue at M11 (P = 0.0055);Gain of catalytic residue at M11 (P = 0.0055);Gain of catalytic residue at M11 (P = 0.0055);Gain of catalytic residue at M11 (P = 0.0055);
MVP		0.98
MPC		0.89
ClinPred		0.57	D
GERP RS		5.8
Varity_R		0.32
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-27114426;