X-152651700-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018558.4(GABRQ):c.1076G>A(p.Arg359Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,208,300 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.000027 (0 hom. 13 hem.)
• Consequence: GABRQ NM_018558.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

Genes affected

GABRQ (HGNC:14454): (gamma-aminobutyric acid type A receptor subunit theta) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes the theta subunit of the GABA A receptor. The gene is mapped to chromosome Xq28 in a cluster of genes including those that encode the alpha 3 and epsilon subunits of the GABA A receptor. [provided by RefSeq, Jul 2017]

MAGEA3-DT (HGNC:56247): (MAGEA3 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028407931).
• BS2: High Hemizygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRQ	NM_018558.4	c.1076G>A	p.Arg359Gln	missense_variant	8/9	ENST00000598523.3
MAGEA3-DT	XR_938525.3	n.157-11906C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRQ	ENST00000598523.3	c.1076G>A	p.Arg359Gln	missense_variant	8/9	1	NM_018558.4	P1
MAGEA3-DT	ENST00000671457.1	n.130-11906C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000534 AC: 6 AN: 112286 Hom.: 0 Cov.: 24 AF XY: 0.0000871 AC XY: 3 AN XY: 34450

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000845

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 20 AN: 183434 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00130

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.0000628

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 30 AN: 1095960 Hom.: 0 Cov.: 30 AF XY: 0.0000360 AC XY: 13 AN XY: 361342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000563

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000714

Gnomad4 OTH exome AF: 0.0000869

GnomAD4 genome AF: 0.0000534 AC: 6 AN: 112340 Hom.: 0 Cov.: 24 AF XY: 0.0000869 AC XY: 3 AN XY: 34514

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000847

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000162

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000109 Hom.: 1

Bravo AF: 0.0000718

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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 04, 2024

The c.1076G>A (p.R359Q) alteration is located in exon 8 (coding exon 8) of the GABRQ gene. This alteration results from a G to A substitution at nucleotide position 1076, causing the arginine (R) at amino acid position 359 to be replaced by a glutamine (Q). 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	0.083
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	2.6
Dann	Benign	0.94
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
Sift4G	Benign	1.0	T
Vest4		0.034
MutPred		0.44		Loss of helix (P = 0.0068);
MVP		0.88
ClinPred		0.016	T
GERP RS		-2.1
gMVP		0.38

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: rs782057587; hg19: chrX-151820163; COSMIC: COSV64780833;