Genetic Variant GPR161:p.Arg492Trp (chr1-168085647-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001375883.1(GPR161):c.1474C>T(p.Arg492Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R492Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GPR161
NM_001375883.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48

Variant links:

Genes affected

GPR161 (HGNC:23694): (G protein-coupled receptor 161) The protein encoded by this gene is an orphan G protein-coupled receptor whose ligand is unknown. This gene is overexpressed in triple-negative breast cancer, and disruption of this gene slows the proliferation of basal breast cancer cells. Therefore, this gene is a potential drug target for triple-negative breast cancer. [provided by RefSeq, Mar 2017]

GPR161 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.21517915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR161	NM_001375883.1 link	c.1474C>T	p.Arg492Trp	missense_variant	Exon 6 of 6	ENST00000682931.1	NP_001362812.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR161	ENST00000682931.1 link	c.1474C>T	p.Arg492Trp	missense_variant	Exon 6 of 6		NM_001375883.1	ENSP00000506967.1		Q8N6U8-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251442

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1474C>T (p.R492W) alteration is located in exon 8 (coding exon 5) of the GPR161 gene. This alteration results from a C to T substitution at nucleotide position 1474, causing the arginine (R) at amino acid position 492 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

0.10

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;.;.;.;T;.;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

D;D;D;D;.;D;D

M_CAP

Benign

0.063

MetaRNN

Benign

0.22

T;T;T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.0

.;.;.;.;L;.;L

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.0

N;N;.;N;N;N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.028

D;D;.;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D;D

Polyphen

0.017

.;.;.;.;B;.;B

Vest4

0.19

MVP

0.85

MPC

0.35

ClinPred

0.16

GERP RS

4.7

Varity_R

0.14

gMVP

0.47

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