chrX-152189917-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000808.4(GABRA3):​c.956C>A​(p.Thr319Asn) 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 (no stars).

Frequency

Genomes: not found (cov: 22)

Consequence

GABRA3
NM_000808.4 missense

Scores

14
2
1

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 9.94
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GABRA3NM_000808.4 linkuse as main transcriptc.956C>A p.Thr319Asn missense_variant 9/10 ENST00000370314.9 NP_000799.1
GABRA3XM_006724811.4 linkuse as main transcriptc.931+7716C>A intron_variant XP_006724874.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GABRA3ENST00000370314.9 linkuse as main transcriptc.956C>A p.Thr319Asn missense_variant 9/101 NM_000808.4 ENSP00000359337 P1
GABRA3ENST00000535043.1 linkuse as main transcriptc.956C>A p.Thr319Asn missense_variant 9/101 ENSP00000443527 P1
GABRA3ENST00000497894.1 linkuse as main transcriptn.27C>A non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

GABRA3-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 03, 2024The GABRA3 c.956C>A variant is predicted to result in the amino acid substitution p.Thr319Asn. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.91
D;D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
.;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.2
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-4.7
D;D
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.81
MutPred
0.75
Loss of glycosylation at T319 (P = 0.0565);Loss of glycosylation at T319 (P = 0.0565);
MVP
0.98
MPC
2.8
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.97
gMVP
0.99

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-151358389; COSMIC: COSV100942443; COSMIC: COSV100942443; API