Variant X-152652835-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_018558.4(GABRQ):c.1453C>T(p.Arg485Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,208,797 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000091 ( 0 hom. 3 hem. )

Consequence

GABRQ
NM_018558.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.382

Variant links:

Genes affected

GABRQ (HGNC:14454): (gamma-aminobutyric acid type A receptor subunit theta) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes the theta subunit of the GABA A receptor. The gene is mapped to chromosome Xq28 in a cluster of genes including those that encode the alpha 3 and epsilon subunits of the GABA A receptor. [provided by RefSeq, Jul 2017]

GABRQ links:

MAGEA3-DT (HGNC:56247): (MAGEA3 divergent transcript)

MAGEA3-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15533048).

BS2

High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRQ	NM_018558.4 linkuse as main transcript	c.1453C>T	p.Arg485Cys	missense_variant	9/9	ENST00000598523.3
MAGEA3-DT	XR_938525.3 linkuse as main transcript	n.157-13041G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRQ	ENST00000598523.3 linkuse as main transcript	c.1453C>T	p.Arg485Cys	missense_variant	9/9	1	NM_018558.4	P1
MAGEA3-DT	ENST00000671457.1 linkuse as main transcript	n.130-13041G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112417

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34575

show subpopulations

Gnomad AFR

AF:

0.0000647

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000327

AC:

AN:

183406

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67850

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:

0.0000611

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.00000912

AC:

AN:

1096380

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

361768

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:

0.0000107

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112417

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34575

show subpopulations

Gnomad4 AFR

AF:

0.0000647

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.1453C>T (p.R485C) alteration is located in exon 9 (coding exon 9) of the GABRQ gene. This alteration results from a C to T substitution at nucleotide position 1453, causing the arginine (R) at amino acid position 485 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.48

Cadd

Benign

Dann

Benign

0.96

FATHMM_MKL

Benign

0.016

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.79

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

Sift4G

Benign

0.086

Vest4

0.085

MutPred

0.47

Gain of helix (P = 0.0078);

MVP

0.71

ClinPred

0.061

GERP RS

2.7

gMVP

0.21

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