10-25221111-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020752.3(GPR158):c.962A>G(p.Asp321Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,605,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: GPR158 NM_020752.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1125043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR158	NM_020752.3	c.962A>G	p.Asp321Gly	missense_variant	2/11	ENST00000376351.4
GPR158	XR_930512.4	n.1382A>G		non_coding_transcript_exon_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR158	ENST00000376351.4	c.962A>G	p.Asp321Gly	missense_variant	2/11	1	NM_020752.3	P2
GPR158	ENST00000650135.1	c.725A>G	p.Asp242Gly	missense_variant	3/12			A2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 250054 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000107 AC: 155 AN: 1452930 Hom.: 0 Cov.: 26 AF XY: 0.000111 AC XY: 80 AN XY: 723314

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000491

EpiControl AF: 0.000237

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 27, 2022

The c.962A>G (p.D321G) alteration is located in exon 2 (coding exon 2) of the GPR158 gene. This alteration results from a A to G substitution at nucleotide position 962, causing the aspartic acid (D) at amino acid position 321 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
Polyphen		0.61	.;P
Vest4		0.53
MVP		0.17
MPC		0.22
ClinPred		0.13	T
GERP RS		5.4
Varity_R		0.18
gMVP		0.69

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: rs372216544; hg19: chr10-25510040;