Variant chrX-151954760-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_004961.4(GABRE):c.1462T>C(p.Phe488Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,209,232 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000042 ( 0 hom. 10 hem. )

Consequence

GABRE
NM_004961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.59

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRE	NM_004961.4 link	c.1462T>C	p.Phe488Leu	missense_variant	9/9	ENST00000370328.4	NP_004952.2	P78334-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GABRE	ENST00000370328.4 link	c.1462T>C	p.Phe488Leu	missense_variant	9/9	1	NM_004961.4	ENSP00000359353.3	P78334-1
GABRE	ENST00000486255.1 link	n.4541T>C		non_coding_transcript_exon_variant	3/3	1
GABRE	ENST00000483564.5 link	n.1112T>C		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

112172

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34326

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000752

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000610

AC:

AN:

180452

Hom.:

AF XY:

0.0000461

AC XY:

AN XY:

65118

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:

0.000136

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000419

AC:

AN:

1097060

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

362474

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:

0.0000547

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112172

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34326

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000752

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.000124

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

Nov 21, 2024

The c.1462T>C (p.F488L) alteration is located in exon 9 (coding exon 9) of the GABRE gene. This alteration results from a T to C substitution at nucleotide position 1462, causing the phenylalanine (F) at amino acid position 488 to be replaced by a leucine (L). 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

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.64

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.9

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MutPred

0.84

Loss of sheet (P = 0.0181);

MVP

0.83

MPC

0.39

ClinPred

0.98

GERP RS

5.7

Varity_R

0.85

gMVP

0.78

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