X-151969707-A-T

Variant names:

• chrX-151969707-A-T
• rs1139916
• NM_004961.4:c.304T>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004961.4(GABRE):​c.304T>A​(p.Ser102Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000024 in 1,206,334 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 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. S102A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000026 (0 hom. 8 hem.)
• Consequence: GABRE NM_004961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 38 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29157704).
• BS2: High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRE	NM_004961.4	c.304T>A	p.Ser102Thr	missense_variant	Exon 3 of 9	ENST00000370328.4	NP_004952.2
GABRE	XM_024452360.2	c.-36T>A		5_prime_UTR_variant	Exon 4 of 10		XP_024308128.1
GABRE	XM_047441959.1	c.-36T>A		5_prime_UTR_variant	Exon 3 of 9		XP_047297915.1
GABRE	XM_047441960.1	c.-36T>A		5_prime_UTR_variant	Exon 2 of 9		XP_047297916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRE	ENST00000370328.4	c.304T>A	p.Ser102Thr	missense_variant	Exon 3 of 9	1	NM_004961.4	ENSP00000359353.3

Frequencies

GnomAD3 genomes AF: 0.00000913 AC: 1 AN: 109521 Hom.: 0 Cov.: 22

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: 0.000405

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000274 AC: 5 AN: 182165 AF XY: 0.0000300

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000492

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 28 AN: 1096813 Hom.: 0 Cov.: 33 AF XY: 0.0000221 AC XY: 8 AN XY: 362225

African (AFR) AF: 0.0000758 AC: 2 AN: 26378

American (AMR) AF: 0.00 AC: 0 AN: 35147

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.0000297 AC: 25 AN: 841213

Other (OTH) AF: 0.00 AC: 0 AN: 46052

GnomAD4 genome AF: 0.00000913 AC: 1 AN: 109521 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31801

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29971

American (AMR) AF: 0.00 AC: 0 AN: 10299

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2625

East Asian (EAS) AF: 0.00 AC: 0 AN: 3452

South Asian (SAS) AF: 0.000405 AC: 1 AN: 2469

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52606

Other (OTH) AF: 0.00 AC: 0 AN: 1479

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 68580

ExAC AF: 0.0000412 AC: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.060	T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.13	T
Polyphen		0.90	P
Vest4		0.065
MutPred		0.39		Gain of glycosylation at S102 (P = 0.0871);
MVP		0.77
MPC		0.10
ClinPred		0.13	T
GERP RS		2.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.32
gMVP		0.35
Mutation Taster		=296/4	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: rs1139916; hg19: chrX-151138179;