Variant X-152255832-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_ModeratePM1PM2PP5

The NM_000808.4(GABRA3):c.497C>T(p.Thr166Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,011 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

GABRA3
NM_000808.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.48

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]

GABRA3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS1

Transcript NM_000808.4 (GABRA3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

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;

PP5

Variant X-152255832-G-A is Pathogenic according to our data. Variant chrX-152255832-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1799557.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 linkuse as main transcript	c.497C>T	p.Thr166Met	missense_variant	5/10	ENST00000370314.9
GABRA3	XM_006724811.4 linkuse as main transcript	c.497C>T	p.Thr166Met	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GABRA3	ENST00000370314.9 linkuse as main transcript	c.497C>T	p.Thr166Met	missense_variant	5/10	1	NM_000808.4	P1
GABRA3	ENST00000535043.1 linkuse as main transcript	c.497C>T	p.Thr166Met	missense_variant	5/10	1		P1
GABRA3	ENST00000417858.1 linkuse as main transcript	n.167C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183003

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67623

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000546

AC:

AN:

1098011

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363425

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

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

Benign

0.15

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.71

D;D

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

.;D

M_CAP

Benign

0.081

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Uncertain

0.0011

MutationAssessor

Benign

0.54

N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.43

Sift

Benign

0.27

T;T

Sift4G

Benign

0.10

T;T

Polyphen

1.0

D;D

Vest4

0.21

MutPred

0.41

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);

MVP

0.98

MPC

1.5

ClinPred

0.27

GERP RS

5.4

Varity_R

0.36

gMVP

0.93

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over