X-151954910-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004961.4(GABRE):c.1312C>T(p.Arg438Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000902 in 1,208,912 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 38 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., 17 hem., cov: 23)

Exomes 𝑓: 0.000059 ( 0 hom. 21 hem. )

Consequence

GABRE
NM_004961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0600

Variant links:

Genes affected

GABRE (HGNC:4085): (gamma-aminobutyric acid type A receptor subunit epsilon) The product of this gene belongs to the ligand-gated ionic channel (TC 1.A.9) family. It encodes the gamma-aminobutyric acid (GABA) A receptor which is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes an epsilon subunit. It is mapped to chromosome Xq28 in a cluster comprised of genes encoding alpha 3, beta 4 and theta subunits of the same receptor. Alternatively spliced transcript variants have been identified, but only one is thought to encode a protein. [provided by RefSeq, Oct 2008]

GABRE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030591607).

BS2

High Hemizygotes in GnomAd at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRE	NM_004961.4 linkuse as main transcript	c.1312C>T	p.Arg438Cys	missense_variant	9/9	ENST00000370328.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRE	ENST00000370328.4 linkuse as main transcript	c.1312C>T	p.Arg438Cys	missense_variant	9/9	1	NM_004961.4	P1	P78334-1
GABRE	ENST00000486255.1 linkuse as main transcript	n.4391C>T		non_coding_transcript_exon_variant	3/3	1
GABRE	ENST00000483564.5 linkuse as main transcript	n.962C>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

111691

Hom.:

Cov.:

AF XY:

0.000502

AC XY:

AN XY:

33881

show subpopulations

Gnomad AFR

AF:

0.00117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00226

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

179870

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

64686

show subpopulations

Gnomad AFR exome

AF:

0.00131

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000948

Gnomad SAS exome

AF:

0.0000540

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.000675

GnomAD4 exome

AF:

0.0000592

AC:

AN:

1097172

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

362582

show subpopulations

Gnomad4 AFR exome

AF:

0.000569

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000994

Gnomad4 SAS exome

AF:

0.0000742

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.000394

AC:

AN:

111740

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

AN XY:

33940

show subpopulations

Gnomad4 AFR

AF:

0.00117

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00227

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000338

Hom.:

Bravo

AF:

0.000370

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

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

Jan 30, 2024

The c.1312C>T (p.R438C) alteration is located in exon 9 (coding exon 9) of the GABRE gene. This alteration results from a C to T substitution at nucleotide position 1312, causing the arginine (R) at amino acid position 438 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

-0.46

BayesDel_noAF

Benign

-0.46

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.18

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.2

REVEL

Benign

0.27

Sift

Benign

0.047

Sift4G

Uncertain

0.053

Polyphen

0.99

Vest4

0.018

MVP

0.71

MPC

0.080

ClinPred

0.016

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.095

gMVP

0.22

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