X-151955050-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004961.4(GABRE):c.1172G>A(p.Arg391His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,088,108 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 5 hem.)
• Consequence: GABRE NM_004961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.42

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.101282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRE	NM_004961.4	c.1172G>A	p.Arg391His	missense_variant	9/9	ENST00000370328.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRE	ENST00000370328.4	c.1172G>A	p.Arg391His	missense_variant	9/9	1	NM_004961.4	P1
GABRE	ENST00000486255.1	n.4251G>A		non_coding_transcript_exon_variant	3/3	1
GABRE	ENST00000483564.5	n.822G>A		non_coding_transcript_exon_variant	4/4	3
GABRE	ENST00000495862.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000230 AC: 25 AN: 1088108 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 5 AN XY: 354908

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.0000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000192

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000251

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome Cov.: 23

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

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

Jan 08, 2024

The c.1172G>A (p.R391H) alteration is located in exon 9 (coding exon 9) of the GABRE gene. This alteration results from a G to A substitution at nucleotide position 1172, causing the arginine (R) at amino acid position 391 to be replaced by a histidine (H). 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	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.89
Dann	Benign	0.96
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.95	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.14
Sift	Benign	0.16	T
Sift4G	Benign	0.20	T
Polyphen		0.017	B
Vest4		0.094
MutPred		0.60		Loss of methylation at R391 (P = 0.0384);
MVP		0.87
MPC		0.072
ClinPred		0.029	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs756791363; hg19: chrX-151123522; COSMIC: COSV100944417; COSMIC: COSV100944417;