X-152652625-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_018558.4(GABRQ):c.1243G>A(p.Gly415Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,097,592 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000073 (0 hom. 4 hem.)
• Consequence: GABRQ NM_018558.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.130

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=0.11804652).
• BP6: Variant X-152652625-G-A is Benign according to our data. Variant chrX-152652625-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2212673.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRQ	NM_018558.4	c.1243G>A	p.Gly415Ser	missense_variant	9/9	ENST00000598523.3
MAGEA3-DT	XR_938525.3	n.157-12831C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRQ	ENST00000598523.3	c.1243G>A	p.Gly415Ser	missense_variant	9/9	1	NM_018558.4	P1
MAGEA3-DT	ENST00000671457.1	n.130-12831C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 183324 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1097592 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 362970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000113

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	5.2
Dann	Benign	0.96
FATHMM_MKL	Benign	0.012	N
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.46	T
Vest4		0.0090
MutPred		0.25		Gain of phosphorylation at G415 (P = 0.012);
MVP		0.81
ClinPred		0.062	T
GERP RS		-1.5
gMVP		0.49

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: rs782079877; hg19: chrX-151821088;