12-12908991-G-C

Variant names:

• chr12-12908991-G-C
• rs139710969
• NM_003979.4:c.742G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003979.4(GPRC5A):​c.742G>C​(p.Ala248Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A248T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPRC5A NM_003979.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.83
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPRC5A	NM_003979.4	c.742G>C	p.Ala248Pro	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.742G>C	p.Ala248Pro	missense_variant	Exon 2 of 4	1	NM_003979.4	ENSP00000014914.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;D;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.0079
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.4	M;.;.
PhyloP100		6.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.4	D;D;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.011	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.88
MutPred		0.57		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.75
MPC		0.29
ClinPred		0.99	D
GERP RS		3.6
PromoterAI		-0.052	Neutral
Varity_R		0.86
gMVP		0.95
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139710969; hg19: chr12-13061925;