Variant chr13-99255452-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001098200.2(GPR18):c.421G>C(p.Ala141Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 1 hom. )

Consequence

GPR18
NM_001098200.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

Variant links:

Genes affected

GPR18 (HGNC:4472): (G protein-coupled receptor 18) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in positive regulation of Rho protein signal transduction and positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway. Predicted to act upstream of or within T cell differentiation; negative regulation of leukocyte chemotaxis; and negative regulation of tumor necrosis factor production. Predicted to be located in plasma membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

GPR18 links:

UBAC2 (HGNC:20486): (UBA domain containing 2) Involved in negative regulation of canonical Wnt signaling pathway and negative regulation of retrograde protein transport, ER to cytosol. Acts upstream of or within protein localization to endoplasmic reticulum. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

UBAC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR18	NM_001098200.2 linkuse as main transcript	c.421G>C	p.Ala141Pro	missense_variant	2/2	ENST00000397470.5
UBAC2	NM_001144072.2 linkuse as main transcript	c.389+10828C>G		intron_variant		ENST00000403766.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR18	ENST00000397470.5 linkuse as main transcript	c.421G>C	p.Ala141Pro	missense_variant	2/2	1	NM_001098200.2	P1
UBAC2	ENST00000403766.8 linkuse as main transcript	c.389+10828C>G		intron_variant		2	NM_001144072.2	P1	Q8NBM4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251314

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.421G>C (p.A141P) alteration is located in exon 3 (coding exon 1) of the GPR18 gene. This alteration results from a G to C substitution at nucleotide position 421, causing the alanine (A) at amino acid position 141 to be replaced by a proline (P). 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

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;T

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

.;D;.

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.8

M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.022

D;D;D

Sift4G

Uncertain

0.015

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.83

MutPred

0.64

Gain of catalytic residue at V145 (P = 0);Gain of catalytic residue at V145 (P = 0);Gain of catalytic residue at V145 (P = 0);

MVP

0.39

MPC

0.47

ClinPred

0.93

GERP RS

5.2

Varity_R

0.74

gMVP

0.94

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over