X-151955472-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004961.4(GABRE):c.1033G>A(p.Ala345Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,209,709 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 91 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 5 hem., cov: 24)
  • Exomes 𝑓: 0.00024 (0 hom. 86 hem.)
• Consequence: GABRE NM_004961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.293

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1597147).
• BS2: High Hemizygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRE	NM_004961.4	c.1033G>A	p.Ala345Thr	missense_variant	8/9	ENST00000370328.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRE	ENST00000370328.4	c.1033G>A	p.Ala345Thr	missense_variant	8/9	1	NM_004961.4	P1

Frequencies

GnomAD3 genomes AF: 0.000160 AC: 18 AN: 112216 Hom.: 0 Cov.: 24 AF XY: 0.000145 AC XY: 5 AN XY: 34408

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: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000319

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000126 AC: 23 AN: 183174 Hom.: 0 AF XY: 0.000177 AC XY: 12 AN XY: 67662

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: 0.000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000243 AC: 267 AN: 1097440 Hom.: 0 Cov.: 31 AF XY: 0.000237 AC XY: 86 AN XY: 362806

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000536

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000271

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000160 AC: 18 AN: 112269 Hom.: 0 Cov.: 24 AF XY: 0.000145 AC XY: 5 AN XY: 34471

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000371

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000319

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000232 Hom.: 9

Bravo AF: 0.000140

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.1033G>A (p.A345T) alteration is located in exon 8 (coding exon 8) of the GABRE gene. This alteration results from a G to A substitution at nucleotide position 1033, causing the alanine (A) at amino acid position 345 to be replaced by a threonine (T). 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	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	4.6
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.90	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.26
Sift	Benign	0.19	T
Sift4G	Benign	0.42	T
Polyphen		0.95	P
Vest4		0.066
MVP		0.88
MPC		0.067
ClinPred		0.048	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.54

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

Other links and lift over

dbSNP: rs147565446; hg19: chrX-151123944; COSMIC: COSV100944298; COSMIC: COSV100944298;