X-152168286-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000808.4(GABRA3):​c.1421A>G​(p.Tyr474Cys) 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 (★).

Frequency

Genomes: not found (cov: 23)

Consequence

GABRA3
NM_000808.4 missense

Scores

13
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.96
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 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant X-152168286-T-C is Pathogenic according to our data. Variant chrX-152168286-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 985441.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-152168286-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GABRA3NM_000808.4 linkuse as main transcriptc.1421A>G p.Tyr474Cys missense_variant 10/10 ENST00000370314.9 NP_000799.1
GABRA3XM_006724811.4 linkuse as main transcriptc.*186A>G 3_prime_UTR_variant 9/9 XP_006724874.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GABRA3ENST00000370314.9 linkuse as main transcriptc.1421A>G p.Tyr474Cys missense_variant 10/101 NM_000808.4 ENSP00000359337 P1
GABRA3ENST00000535043.1 linkuse as main transcriptc.1421A>G p.Tyr474Cys missense_variant 10/101 ENSP00000443527 P1
ENST00000453915.1 linkuse as main transcriptn.501+3698T>C intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 17, 2018- -
Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 22, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D;D
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Pathogenic
3.0
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-7.8
D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.95
MutPred
0.86
Gain of catalytic residue at W475 (P = 0.032);Gain of catalytic residue at W475 (P = 0.032);
MVP
0.98
MPC
1.3
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.93
gMVP
0.94

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1936960785; hg19: chrX-151336758; API