Variant X-152208105-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The ENST00000370314.9(GABRA3):c.674T>C(p.Leu225Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,097,179 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 4 hem. )

Consequence

GABRA3
ENST00000370314.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.72

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_benign. Variant got -3 ACMG points.

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 ENST00000370314.9

BP4

Computational evidence support a benign effect (MetaRNN=0.42301708).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA3	NM_000808.4 linkuse as main transcript	c.674T>C	p.Leu225Pro	missense_variant	7/10	ENST00000370314.9	NP_000799.1
GABRA3	XM_006724811.4 linkuse as main transcript	c.674T>C	p.Leu225Pro	missense_variant	7/9		XP_006724874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA3	ENST00000370314.9 linkuse as main transcript	c.674T>C	p.Leu225Pro	missense_variant	7/10	1	NM_000808.4	ENSP00000359337	P1
GABRA3	ENST00000535043.1 linkuse as main transcript	c.674T>C	p.Leu225Pro	missense_variant	7/10	1		ENSP00000443527	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183400

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67836

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1097179

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362551

show subpopulations

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:

0.0000119

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

.;D

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.42

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.28

N;N

REVEL

Uncertain

0.44

Sift

Benign

0.19

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.59

P;P

Vest4

0.46

MutPred

0.51

Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);

MVP

0.97

MPC

2.6

ClinPred

0.45

GERP RS

5.4

Varity_R

0.31

gMVP

0.97

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