chr3-154421067-C-T

Position:

• chr3-154421067-C-T

Variant summary

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

The NM_001038705.3(GPR149):​c.1595G>A​(p.Arg532Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GPR149 NM_001038705.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.93

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]

ACMG classification

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	c.1595G>A	p.Arg532Lys	missense_variant	3/4	ENST00000389740.3	NP_001033794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR149	ENST00000389740.3	c.1595G>A	p.Arg532Lys	missense_variant	3/4	1	NM_001038705.3	ENSP00000374390.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460148 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726378

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

May 15, 2024

The c.1595G>A (p.R532K) alteration is located in exon 3 (coding exon 3) of the GPR149 gene. This alteration results from a G to A substitution at nucleotide position 1595, causing the arginine (R) at amino acid position 532 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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Benign	0.0	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.47		Gain of methylation at R532 (P = 7e-04);
MVP		0.18
MPC		0.32
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.58
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-154138856;