chrX-152197639-C-G

Variant names:

• chrX-152197639-C-G
• rs1937406707
• NM_000808.4:c.925G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000808.4(GABRA3):​c.925G>C​(p.Val309Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V309A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GABRA3 NM_000808.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86
• Publications: 0 publications found

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]

GABRA3 Gene-Disease associations (from GenCC):

• epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000808.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA3	NM_000808.4	MANE Select	c.925G>C	p.Val309Leu	missense	Exon 8 of 10	NP_000799.1	P34903

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA3	ENST00000370314.9	TSL:1 MANE Select	c.925G>C	p.Val309Leu	missense	Exon 8 of 10	ENSP00000359337.4	P34903
	GABRA3	ENST00000535043.1	TSL:1	c.925G>C	p.Val309Leu	missense	Exon 8 of 10	ENSP00000443527.1	P34903
	GABRA3	ENST00000862742.1		c.925G>C	p.Val309Leu	missense	Exon 9 of 11	ENSP00000532801.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.017	D
Sift4G	Benign	0.087	T
Polyphen		0.99	D
Vest4		0.70
MutPred		0.51		Loss of sheet (P = 0.0817)
MVP		0.72
MPC		2.6
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.51
gMVP		0.98
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs1937406707; hg19: chrX-151366111;