12-12908725-G-A

Variant names:

• chr12-12908725-G-A
• rs1863971026
• NM_003979.4:c.476G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003979.4(GPRC5A):​c.476G>A​(p.Arg159Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPRC5A NM_003979.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64

Genes affected

GPRC5A (HGNC:9836): (G protein-coupled receptor class C group 5 member A) This gene encodes a member of the type 3 G protein-coupling receptor family, characterized by the signature 7-transmembrane domain motif. The encoded protein may be involved in interaction between retinoid acid and G protein signalling pathways. Retinoic acid plays a critical role in development, cellular growth, and differentiation. This gene may play a role in embryonic development and epithelial cell differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPRC5A	NM_003979.4	c.476G>A	p.Arg159Lys	missense_variant	Exon 2 of 4	ENST00000014914.6	NP_003970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPRC5A	ENST00000014914.6	c.476G>A	p.Arg159Lys	missense_variant	Exon 2 of 4	1	NM_003979.4	ENSP00000014914.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.476G>A (p.R159K) alteration is located in exon 2 (coding exon 1) of the GPRC5A gene. This alteration results from a G to A substitution at nucleotide position 476, causing the arginine (R) at amino acid position 159 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	0.16
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;D;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.38
Sift	Benign	0.088	T;T;.
Sift4G	Benign	0.085	T;T;.
Polyphen		0.62	P;.;.
Vest4		0.14
MutPred		0.78		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.65
MPC		0.050
ClinPred		0.87	D
GERP RS		4.7
Varity_R		0.19
gMVP		0.43

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

Other links and lift over

dbSNP: rs1863971026; hg19: chr12-13061659;