12-12908793-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003979.4(GPRC5A):c.544A>G(p.Thr182Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,614,018 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0059 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (77 hom.)
• Consequence: GPRC5A NM_003979.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.24

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014664352).
• BP6: Variant 12-12908793-A-G is Benign according to our data. Variant chr12-12908793-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2642742.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRC5A	NM_003979.4	c.544A>G	p.Thr182Ala	missense_variant	2/4	ENST00000014914.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRC5A	ENST00000014914.6	c.544A>G	p.Thr182Ala	missense_variant	2/4	1	NM_003979.4	P1

Frequencies

GnomAD3 genomes AF: 0.00593 AC: 902 AN: 152036 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00437

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00931

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00610 AC: 1534 AN: 251400 Hom.: 13 AF XY: 0.00640 AC XY: 870 AN XY: 135868

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00686

Gnomad FIN exome AF: 0.00402

Gnomad NFE exome AF: 0.00894

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00861 AC: 12591 AN: 1461866 Hom.: 77 Cov.: 33 AF XY: 0.00854 AC XY: 6210 AN XY: 727236

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00362

Gnomad4 ASJ exome AF: 0.00474

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00740

Gnomad4 FIN exome AF: 0.00389

Gnomad4 NFE exome AF: 0.00982

Gnomad4 OTH exome AF: 0.00800

GnomAD4 genome AF: 0.00593 AC: 903 AN: 152152 Hom.: 4 Cov.: 32 AF XY: 0.00619 AC XY: 460 AN XY: 74366

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00550

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00437

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.00931

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00793 Hom.: 10

Bravo AF: 0.00546

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00628 AC: 763

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00971

EpiControl AF: 0.00895

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

GPRC5A: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	0.012
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.60	T;T;T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.97	L;.;.
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.23	N;N;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		0.010	B;.;.
Vest4		0.26
MVP		0.66
MPC		0.044
ClinPred		0.061	T
GERP RS		5.4
Varity_R		0.27
gMVP		0.23

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: rs12368599; hg19: chr12-13061727; COSMIC: COSV105002116; COSMIC: COSV105002116;