15-26883178-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.221A>G(p.Gln74Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q74K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GABRA5 NM_000810.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABRA5
• BP4: Computational evidence support a benign effect (MetaRNN=0.39733297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA5	NM_000810.4	c.221A>G	p.Gln74Arg	missense_variant	5/11	ENST00000335625.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA5	ENST00000335625.10	c.221A>G	p.Gln74Arg	missense_variant	5/11	1	NM_000810.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2021

The c.221A>G (p.Q74R) alteration is located in exon 5 (coding exon 3) of the GABRA5 gene. This alteration results from a A to G substitution at nucleotide position 221, causing the glutamine (Q) at amino acid position 74 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T;T;.;.;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.036
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.090	N;N;.;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.14	T;T;T;T;D;T;T;T
Sift4G	Benign	0.40	T;T;T;T;D;T;T;T
Polyphen		0.019	B;B;.;B;.;.;.;.
Vest4		0.54
MutPred		0.32		Gain of phosphorylation at T77 (P = 0.0794);Gain of phosphorylation at T77 (P = 0.0794);.;Gain of phosphorylation at T77 (P = 0.0794);Gain of phosphorylation at T77 (P = 0.0794);Gain of phosphorylation at T77 (P = 0.0794);Gain of phosphorylation at T77 (P = 0.0794);.;
MVP		0.79
MPC		1.1
ClinPred		0.92	D
GERP RS		4.3
Varity_R		0.16
gMVP		0.73

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: chr15-27128325;