rs112948541

Variant names:

• chr12-12908347-C-T
• rs112948541
• NM_003979.4:c.98C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_003979.4(GPRC5A):​c.98C>T​(p.Thr33Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T33T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: GPRC5A NM_003979.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36475772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPRC5A	NM_003979.4	c.98C>T	p.Thr33Met	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.98C>T	p.Thr33Met	missense_variant	Exon 2 of 4	1	NM_003979.4	ENSP00000014914.6

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 17 AN: 251340 AF XY: 0.0000515

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727152

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.000268 AC: 12 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111856

Other (OTH) AF: 0.000149 AC: 9 AN: 60384

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74456

African (AFR) AF: 0.0000722 AC: 3 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.98C>T (p.T33M) 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 98, causing the threonine (T) at amino acid position 33 to be replaced by a methionine (M). 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	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.
PhyloP100		7.8
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0080	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.29
MVP		0.48
MPC		0.22
ClinPred		0.23	T
GERP RS		5.4
PromoterAI		0.050	Neutral
Varity_R		0.079
gMVP		0.67
Mutation Taster		=81/19	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: rs112948541; hg19: chr12-13061281;