X-152647085-C-G

Position:

• chrX-152647085-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018558.4(GABRQ):​c.444C>G​(p.Ser148Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,096,573 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: GABRQ NM_018558.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRQ	NM_018558.4	c.444C>G	p.Ser148Arg	missense_variant	4/9	ENST00000598523.3	NP_061028.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRQ	ENST00000598523.3	c.444C>G	p.Ser148Arg	missense_variant	4/9	1	NM_018558.4	ENSP00000469332.1
MAGEA3-DT	ENST00000671457.1	n.130-7291G>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096573 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 361969

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000166

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

Nov 13, 2024

The c.444C>G (p.S148R) alteration is located in exon 4 (coding exon 4) of the GABRQ gene. This alteration results from a C to G substitution at nucleotide position 444, causing the serine (S) at amino acid position 148 to be replaced by an arginine (R). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.43	D
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.0040	D
Vest4		0.53
MutPred		0.63		Gain of methylation at K149 (P = 0.0645);
MVP		0.91
ClinPred		0.99	D
GERP RS		5.2
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1930907145; hg19: chrX-151815546;