15-26883496-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000810.4(GABRA5):c.436A>G(p.Met146Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA5 NM_000810.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.12

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABRA5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA5	NM_000810.4	c.436A>G	p.Met146Val	missense_variant	6/11	ENST00000335625.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA5	ENST00000335625.10	c.436A>G	p.Met146Val	missense_variant	6/11	1	NM_000810.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;T;T;.;.
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.70	N;N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	N;N;D;N;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.018	D;D;D;D;D;D
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.20	B;B;.;B;.;.
Vest4		0.84
MutPred		0.47		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.94
MPC		1.1
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.75

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: chr15-27128643;