chrX-152208054-T-A

Position:

• chrX-152208054-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000808.4(GABRA3):​c.725A>T​(p.Gln242Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GABRA3 NM_000808.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.62

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Extracellular (size 247) in uniprot entity GBRA3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000808.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant X-152208054-T-A is Pathogenic according to our data. Variant chrX-152208054-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1799560.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA3	NM_000808.4	c.725A>T	p.Gln242Leu	missense_variant	7/10	ENST00000370314.9
GABRA3	XM_006724811.4	c.725A>T	p.Gln242Leu	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA3	ENST00000370314.9	c.725A>T	p.Gln242Leu	missense_variant	7/10	1	NM_000808.4	P1
GABRA3	ENST00000535043.1	c.725A>T	p.Gln242Leu	missense_variant	7/10	1		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	D;D
Vest4		0.95
MutPred		0.76		Loss of disorder (P = 0.0599);Loss of disorder (P = 0.0599);
MVP		0.94
MPC		2.5
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.97

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-151376526;