3-154338270-C-T

Position:

chr3-154338270-C-T

Variant summary

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

The NM_001038705.3(GPR149):c.1625G>A(p.Arg542His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00003 in 1,533,730 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

GPR149
NM_001038705.3 missense, splice_region

Scores

Splicing: ADA: 0.9893

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83

Variant links:

Genes affected

GPR149 (HGNC:23627): (G protein-coupled receptor 149) This gene encodes a seven-transmembrane G protein coupled receptor (GPCR) class A family member. Although categorized as a class A GPCR, the encoded protein lacks the first two charged amino acids of the highly conserved Asp-Arg-Tyr (DRY) motif found in the third transmembrane helix of class A receptors which is important for efficient G protein-coupled signal transduction. Mice with a knockout of the orthologous gene are viable and have normal maturation of the ovarian follicle, but show enhanced fertility and ovulation. All GPCRs have a common structural architecture consisting of seven transmembrane alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptor, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes. [provided by RefSeq, Jul 2017]

GPR149 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/exons	MANE	Protein	UniProt
GPR149	NM_001038705.3 linkuse as main transcript	c.1625G>A	p.Arg542His	missense_variant, splice_region_variant	4/4	ENST00000389740.3	NP_001033794.1	Q86SP6Q2MKA6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR149	ENST00000389740.3 linkuse as main transcript	c.1625G>A	p.Arg542His	missense_variant, splice_region_variant	4/4	1	NM_001038705.3	ENSP00000374390.2		Q86SP6

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000201

AC:

AN:

198614

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

108304

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:

0.0000417

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000275

AC:

AN:

1381458

Hom.:

Cov.:

AF XY:

0.0000250

AC XY:

AN XY:

679992

show subpopulations

Gnomad4 AFR exome

AF:

0.0000328

Gnomad4 AMR exome

AF:

0.0000970

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.0000137

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000529

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

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:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2022

The c.1625G>A (p.R542H) alteration is located in exon 4 (coding exon 4) of the GPR149 gene. This alteration results from a G to A substitution at nucleotide position 1625, causing the arginine (R) at amino acid position 542 to be replaced by a histidine (H). 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

0.25

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.2

REVEL

Benign

0.21

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.79

MVP

0.12

MPC

0.54

ClinPred

0.77

GERP RS

4.9

Varity_R

0.27

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.030

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