X-151954807-C-T

Variant names:

• chrX-151954807-C-T
• rs80186670
• NM_004961.4:c.1415G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004961.4(GABRE):​c.1415G>A​(p.Arg472His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,210,161 control chromosomes in the GnomAD database, including 9 homozygotes. There are 1,080 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., 46 hem., cov: 23)
  • Exomes 𝑓: 0.0029 (8 hom. 1034 hem.)
• Consequence: GABRE NM_004961.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.51

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011199564).
• BP6: Variant X-151954807-C-T is Benign according to our data. Variant chrX-151954807-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3043062.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 46 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRE	NM_004961.4	c.1415G>A	p.Arg472His	missense_variant	Exon 9 of 9	ENST00000370328.4	NP_004952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRE	ENST00000370328.4	c.1415G>A	p.Arg472His	missense_variant	Exon 9 of 9	1	NM_004961.4	ENSP00000359353.3
GABRE	ENST00000486255.1	n.4494G>A		non_coding_transcript_exon_variant	Exon 3 of 3	1
GABRE	ENST00000483564.5	n.1065G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3
GABRE	ENST00000495862.1	n.*246G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 158 AN: 112307 Hom.: 1 Cov.: 23 AF XY: 0.00134 AC XY: 46 AN XY: 34455

Gnomad AFR AF: 0.000259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000375

Gnomad ASJ AF: 0.00452

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000741

Gnomad FIN AF: 0.000812

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.00185 AC: 339 AN: 182948 Hom.: 1 AF XY: 0.00197 AC XY: 133 AN XY: 67486

Gnomad AFR exome AF: 0.000382

Gnomad AMR exome AF: 0.000621

Gnomad ASJ exome AF: 0.00335

Gnomad EAS exome AF: 0.000362

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00276

Gnomad NFE exome AF: 0.00250

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.00285 AC: 3129 AN: 1097801 Hom.: 8 Cov.: 31 AF XY: 0.00285 AC XY: 1034 AN XY: 363159

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.000682

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.000199

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.00274

Gnomad4 NFE exome AF: 0.00321

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.00141 AC: 158 AN: 112360 Hom.: 1 Cov.: 23 AF XY: 0.00133 AC XY: 46 AN XY: 34518

Gnomad4 AFR AF: 0.000258

Gnomad4 AMR AF: 0.000374

Gnomad4 ASJ AF: 0.00452

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000743

Gnomad4 FIN AF: 0.000812

Gnomad4 NFE AF: 0.00235

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.00238 Hom.: 101

Bravo AF: 0.00120

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00519 AC: 15

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00223 AC: 15

ExAC AF: 0.00189 AC: 229

EpiCase AF: 0.00245

EpiControl AF: 0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GABRE-related disorder Benign:1

Nov 26, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.35
Sift	Benign	0.039	D
Sift4G	Uncertain	0.011	D
Polyphen		0.39	B
Vest4		0.040
MVP		0.92
MPC		0.33
ClinPred		0.050	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.34

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: rs80186670; hg19: chrX-151123279; COSMIC: COSV64819276; COSMIC: COSV64819276;