Genetic Variant GPR3:p.Arg222His (chr1-27394463-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005281.4(GPR3):c.665G>A(p.Arg222His) variant causes a missense change. The variant allele was found at a frequency of 0.00289 in 1,613,992 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.015 ( 49 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 45 hom. )

Consequence

GPR3
NM_005281.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.87

Variant links:

Genes affected

GPR3 (HGNC:4484): (G protein-coupled receptor 3) This gene is a member of the G protein-coupled receptor family and is found in the cell membrane. G protein-coupled receptors, characterized by a seven transmembrane domain motif, are involved in translating outside signals into G protein mediated intracellular effects. The encoded protein activates adenylate cyclase and modulates amyloid-beta production in a mouse model, suggesting that it may play a role in Alzheimer's disease. [provided by RefSeq, Oct 2012]

GPR3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010298997).

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR3	NM_005281.4 link	c.665G>A	p.Arg222His	missense_variant	Exon 2 of 2	ENST00000374024.4	NP_005272.1	P46089F1DAM5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR3	ENST00000374024.4 link	c.665G>A	p.Arg222His	missense_variant	Exon 2 of 2	1	NM_005281.4	ENSP00000363136.3		P46089

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2283

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0517

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00408

AC:

1024

AN:

251244

Hom.:

AF XY:

0.00292

AC XY:

396

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.0538

Gnomad AMR exome

AF:

0.00330

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00162

AC:

2373

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1055

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0545

Gnomad4 AMR exome

AF:

0.00389

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.00373

GnomAD4 genome

AF:

0.0150

AC:

2287

AN:

152240

Hom.:

Cov.:

AF XY:

0.0148

AC XY:

1100

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0516

Gnomad4 AMR

AF:

0.00706

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00284

Hom.:

Bravo

AF:

0.0176

ESP6500AA

AF:

0.0515

AC:

227

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00492

AC:

597

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.15

Sift

Benign

0.036

Sift4G

Benign

0.13

Polyphen

0.83

Vest4

0.17

MVP

0.75

MPC

0.52

ClinPred

0.048

GERP RS

4.7

Varity_R

0.29

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over