X-152197768-T-C

Variant names:

• chrX-152197768-T-C
• NM_000808.4:c.796A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000808.4(GABRA3):​c.796A>G​(p.Thr266Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,094,933 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: GABRA3 NM_000808.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

Genes affected

GABRA3 (HGNC:4077): (gamma-aminobutyric acid type A receptor subunit alpha3) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA3	NM_000808.4	c.796A>G	p.Thr266Ala	missense_variant	Exon 8 of 10	ENST00000370314.9	NP_000799.1
GABRA3	XM_006724811.4	c.796A>G	p.Thr266Ala	missense_variant	Exon 8 of 9		XP_006724874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA3	ENST00000370314.9	c.796A>G	p.Thr266Ala	missense_variant	Exon 8 of 10	1	NM_000808.4	ENSP00000359337.4
GABRA3	ENST00000535043.1	c.796A>G	p.Thr266Ala	missense_variant	Exon 8 of 10	1		ENSP00000443527.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1094933 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 360383

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.796A>G (p.T266A) alteration is located in exon 8 (coding exon 7) of the GABRA3 gene. This alteration results from a A to G substitution at nucleotide position 796, causing the threonine (T) at amino acid position 266 to be replaced by an alanine (A). 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	0.24
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.9	M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.095	T;T
Polyphen		0.99	D;D
Vest4		0.75
MutPred		0.40		Loss of glycosylation at T266 (P = 0.0207);Loss of glycosylation at T266 (P = 0.0207);
MVP		0.95
MPC		2.6
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.56
gMVP		0.95

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: chrX-151366240;