Genetic Variant GPR174:p.Leu155Phe (chrX-79171470-C-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_032553.3(GPR174):c.463C>T(p.Leu155Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,911 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

GPR174
NM_032553.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.19

Variant links:

Genes affected

GPR174 (HGNC:30245): (G protein-coupled receptor 174) This gene encodes a protein belonging to the G protein-coupled receptor superfamily. These proteins are characterized by the presence of seven alpha-helical transmembrane domains, and they activate or interact with various endogenous or exogenous ligands, including neurotransmitters, hormones, and odorant and taste substances. This family member is classified as an orphan receptor because the cognate ligand has not been identified. [provided by RefSeq, Sep 2011]

GPR174 links:

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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
GPR174	NM_032553.3 link	c.463C>T	p.Leu155Phe	missense_variant	Exon 3 of 3	ENST00000645147.2	NP_115942.1	Q9BXC1
GPR174	XM_047442579.1 link	c.463C>T	p.Leu155Phe	missense_variant	Exon 3 of 3		XP_047298535.1
GPR174	XM_047442580.1 link	c.463C>T	p.Leu155Phe	missense_variant	Exon 2 of 2		XP_047298536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR174	ENST00000645147.2 link	c.463C>T	p.Leu155Phe	missense_variant	Exon 3 of 3		NM_032553.3	ENSP00000494310.1		Q9BXC1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182871

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67533

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097911

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363299

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

EpiCase

AF:

0.000109

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

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.463C>T (p.L155F) alteration is located in exon 1 (coding exon 1) of the GPR174 gene. This alteration results from a C to T substitution at nucleotide position 463, causing the leucine (L) at amino acid position 155 to be replaced by a phenylalanine (F). 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

0.27

BayesDel_addAF

Benign

-0.0043

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.030

T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.57

.;T

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.9

.;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.0070

.;D

Sift4G

Uncertain

0.011

.;D

Polyphen

1.0

D;D

Vest4

0.14

MutPred

0.58

Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);

MVP

0.48

MPC

0.40

ClinPred

0.82

GERP RS

4.9

Varity_R

0.63

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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