12-12908277-C-T

Variant names:

• chr12-12908277-C-T
• rs202096166
• NM_003979.4:c.28C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003979.4(GPRC5A):​c.28C>T​(p.Arg10Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000432 in 1,598,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: GPRC5A NM_003979.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11389148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPRC5A	NM_003979.4	c.28C>T	p.Arg10Cys	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.28C>T	p.Arg10Cys	missense_variant	Exon 2 of 4	1	NM_003979.4	ENSP00000014914.6

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000378 AC: 9 AN: 237864 AF XY: 0.0000469

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000429 AC: 62 AN: 1446788 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 29 AN XY: 718276

African (AFR) AF: 0.0000301 AC: 1 AN: 33260

American (AMR) AF: 0.0000233 AC: 1 AN: 42918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24874

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39592

South Asian (SAS) AF: 0.000121 AC: 10 AN: 82952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.0000416 AC: 46 AN: 1104898

Other (OTH) AF: 0.0000502 AC: 3 AN: 59784

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.28C>T (p.R10C) alteration is located in exon 2 (coding exon 1) of the GPRC5A gene. This alteration results from a C to T substitution at nucleotide position 28, causing the arginine (R) at amino acid position 10 to be replaced by a cysteine (C). 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	0.26
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M;.;.
PhyloP100		1.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.67	N;N;.
REVEL	Benign	0.13
Sift	Benign	0.17	T;T;.
Sift4G	Uncertain	0.058	T;D;.
Polyphen		0.99	D;.;.
Vest4		0.31
MutPred		0.38		Loss of MoRF binding (P = 0.0164);Loss of MoRF binding (P = 0.0164);Loss of MoRF binding (P = 0.0164);
MVP		0.43
MPC		0.14
ClinPred		0.13	T
GERP RS		-1.2
PromoterAI		-0.047	Neutral
Varity_R		0.039
gMVP		0.59
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs202096166; hg19: chr12-13061211;