Genetic Variant GABRE:p.Glu435Asp (chrX-151954917-C-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004961.4(GABRE):c.1305G>C(p.Glu435Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000852 in 1,208,785 control chromosomes in the GnomAD database, including 10 homozygotes. There are 263 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 5 hom., 132 hem., cov: 23)

Exomes 𝑓: 0.00049 ( 5 hom. 131 hem. )

Consequence

GABRE
NM_004961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.535

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035134554).

BP6

Variant X-151954917-C-G is Benign according to our data. Variant chrX-151954917-C-G is described in ClinVar as [Benign]. Clinvar id is 720972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRE	NM_004961.4 link	c.1305G>C	p.Glu435Asp	missense_variant	Exon 9 of 9	ENST00000370328.4	NP_004952.2	P78334-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRE	ENST00000370328.4 link	c.1305G>C	p.Glu435Asp	missense_variant	Exon 9 of 9	1	NM_004961.4	ENSP00000359353.3		P78334-1

Frequencies

GnomAD3 genomes

AF:

0.00439

AC:

490

AN:

111738

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

132

AN XY:

33892

show subpopulations

Gnomad AFR

AF:

0.0151

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00227

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00422

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00126

AC:

225

AN:

179165

Hom.:

AF XY:

0.000703

AC XY:

AN XY:

64043

show subpopulations

Gnomad AFR exome

AF:

0.0156

Gnomad AMR exome

AF:

0.000773

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:

0.0000251

Gnomad OTH exome

AF:

0.000226

GnomAD4 exome

AF:

0.000493

AC:

541

AN:

1096996

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

131

AN XY:

362420

show subpopulations

Gnomad4 AFR exome

AF:

0.0147

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000371

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000618

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.00437

AC:

489

AN:

111789

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

132

AN XY:

33953

show subpopulations

Gnomad4 AFR

AF:

0.0150

Gnomad4 AMR

AF:

0.00226

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.00513

ESP6500AA

AF:

0.0141

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00124

AC:

151

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 09, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.18

DANN

Benign

0.84

DEOGEN2

Benign

0.13

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0035

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.86

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.88

REVEL

Benign

0.20

Sift

Benign

0.22

Sift4G

Benign

0.60

Polyphen

0.18

Vest4

0.064

MutPred

0.30

Loss of glycosylation at P437 (P = 0.1089);

MVP

0.68

MPC

0.095

ClinPred

0.0090

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.083

gMVP

0.17

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