X-151955460-C-T

Variant names:

• chrX-151955460-C-T
• rs774731784
• NM_004961.4:c.1045G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004961.4(GABRE):​c.1045G>A​(p.Val349Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,209,946 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V349F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000013 (0 hom. 3 hem.)
• Consequence: GABRE NM_004961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.583
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039436758).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRE	NM_004961.4	MANE Select	c.1045G>A	p.Val349Ile	missense	Exon 8 of 9	NP_004952.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRE	ENST00000370328.4	TSL:1 MANE Select	c.1045G>A	p.Val349Ile	missense	Exon 8 of 9	ENSP00000359353.3	P78334-1
	GABRE	ENST00000486255.1	TSL:1	n.4124G>A		non_coding_transcript_exon	Exon 2 of 3
	GABRE	ENST00000462018.1	TSL:3	n.587G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112300 Hom.: 0 Cov.: 24

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: 0.0000375

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1097646 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363000

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841601

Other (OTH) AF: 0.0000434 AC: 2 AN: 46080

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112300 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34472

African (AFR) AF: 0.00 AC: 0 AN: 30852

American (AMR) AF: 0.00 AC: 0 AN: 10664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6153

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53294

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.010
DANN	Benign	0.79
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.58
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Polyphen		0.23	B
Vest4		0.062
MutPred		0.45		Gain of helix (P = 0.1736)
MVP		0.52
MPC		0.052
ClinPred		0.041	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.037
gMVP		0.33
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs774731784; hg19: chrX-151123932; COSMIC: COSV64819046; COSMIC: COSV64819046;