3-154421204-G-T

Position:

chr3-154421204-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001038705.3(GPR149):c.1458C>A(p.Asn486Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

GPR149
NM_001038705.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06797457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR149	NM_001038705.3 linkuse as main transcript	c.1458C>A	p.Asn486Lys	missense_variant	3/4	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.1458C>A	p.Asn486Lys	missense_variant	3/4	1	NM_001038705.3	ENSP00000374390.2		Q86SP6

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249194

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151802

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74124

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000546

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.1458C>A (p.N486K) alteration is located in exon 3 (coding exon 3) of the GPR149 gene. This alteration results from a C to A substitution at nucleotide position 1458, causing the asparagine (N) at amino acid position 486 to be replaced by a lysine (K). 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

0.081

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.47

DANN

Benign

0.47

DEOGEN2

Benign

0.059

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0

LIST_S2

Benign

0.30

M_CAP

Benign

0.0049

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.47

REVEL

Benign

0.048

Sift

Benign

0.61

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.092

MutPred

0.21

Loss of ubiquitination at K488 (P = 0.02);

MVP

0.030

MPC

0.12

ClinPred

0.027

GERP RS

0.99

Varity_R

0.047

gMVP

0.099

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