Genetic Variant GPR158:p.Gly110Trp (chr10-25175748-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_020752.3(GPR158):c.328G>T(p.Gly110Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000788 in 1,611,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

GPR158
NM_020752.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.69

Variant links:

Genes affected

GPR158 (HGNC:23689): (G protein-coupled receptor 158) Predicted to enable G protein-coupled receptor activity. Predicted to act upstream of or within G protein-coupled receptor signaling pathway and protein localization to plasma membrane. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

GPR158 links:

GPR158-AS1 (HGNC:44163): (GPR158 antisense RNA 1)

GPR158-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
GPR158	NM_020752.3 link	c.328G>T	p.Gly110Trp	missense_variant	Exon 1 of 11	ENST00000376351.4	NP_065803.2	Q5T848
GPR158-AS1	NR_027333.2 link	n.529C>A		non_coding_transcript_exon_variant	Exon 1 of 2
GPR158	XR_930512.4 link	n.748G>T		non_coding_transcript_exon_variant	Exon 1 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GPR158	ENST00000376351.4 link	c.328G>T	p.Gly110Trp	missense_variant	Exon 1 of 11	1	NM_020752.3	ENSP00000365529.3	Q5T848
GPR158	ENST00000650135.1 link	c.91G>T	p.Gly31Trp	missense_variant	Exon 2 of 12			ENSP00000498176.1	A0A3B3IUC3
GPR158-AS1	ENST00000449643.1 link	n.529C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000225

AC:

AN:

244866

Hom.:

AF XY:

0.000240

AC XY:

AN XY:

133232

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000818

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000729

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.0000726

AC:

106

AN:

1459140

Hom.:

Cov.:

AF XY:

0.0000868

AC XY:

AN XY:

726052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000649

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000138

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.328G>T (p.G110W) alteration is located in exon 1 (coding exon 1) of the GPR158 gene. This alteration results from a G to T substitution at nucleotide position 328, causing the glycine (G) at amino acid position 110 to be replaced by a tryptophan (W). 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

0.28

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.59

T;T

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.1

.;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

.;D

Vest4

0.79

MutPred

0.56

.;Loss of disorder (P = 0.0345);

MVP

0.27

MPC

2.0

ClinPred

0.27

GERP RS

4.5

Varity_R

0.74

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over