chrX-152168336-T-G

Position:

• chrX-152168336-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000808.4(GABRA3):​c.1371A>C​(p.Lys457Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,934 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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: 0.132

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]

ENSG00000231937 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA3	NM_000808.4	c.1371A>C	p.Lys457Asn	missense_variant	10/10	ENST00000370314.9	NP_000799.1
GABRA3	XM_006724811.4	c.*136A>C		3_prime_UTR_variant	9/9		XP_006724874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA3	ENST00000370314.9	c.1371A>C	p.Lys457Asn	missense_variant	10/10	1	NM_000808.4	ENSP00000359337.4
GABRA3	ENST00000535043.1	c.1371A>C	p.Lys457Asn	missense_variant	10/10	1		ENSP00000443527.1
ENSG00000231937	ENST00000453915.1	n.501+3748T>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097934 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363292

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

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

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 09, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features (MIM#301091). (I) 0110 - This gene is associated with X-linked disease. Males are more severely affected and there have been reports of asymptomatic female carriers (PMID: 29053855). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to asparagine. (I) 0253 - This variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 (1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (1 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated neurotransmitter-gated ion-channel transmembrane domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.022	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.050	T;T
Polyphen		0.99	D;D
Vest4		0.44
MutPred		0.51		Loss of methylation at K457 (P = 0.0025);Loss of methylation at K457 (P = 0.0025);
MVP		0.99
MPC		1.0
ClinPred		0.95	D
GERP RS		0.77
Varity_R		0.56
gMVP		0.87

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-151336808; COSMIC: COSV64800563;