chr13-99255452-C-G

Variant names:

• chr13-99255452-C-G
• rs755502855
• NM_001098200.2:c.421G>C

Variant summary

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

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83
• Publications: 1 publications found

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]

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]

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, 0.812

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098200.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR18	NM_001098200.2	MANE Select	c.421G>C	p.Ala141Pro	missense	Exon 2 of 2	NP_001091670.1	Q14330
	UBAC2	NM_001144072.2	MANE Select	c.389+10828C>G		intron	N/A	NP_001137544.1	Q8NBM4-1
	GPR18	NM_005292.4		c.421G>C	p.Ala141Pro	missense	Exon 3 of 3	NP_005283.1	Q14330

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR18	ENST00000397470.5	TSL:1 MANE Select	c.421G>C	p.Ala141Pro	missense	Exon 2 of 2	ENSP00000380610.2	Q14330
	GPR18	ENST00000340807.3	TSL:1	c.421G>C	p.Ala141Pro	missense	Exon 3 of 3	ENSP00000343428.3	Q14330
	GPR18	ENST00000397473.7	TSL:1	c.421G>C	p.Ala141Pro	missense	Exon 3 of 3	ENSP00000380613.2	Q14330

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251314 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461878 Hom.: 1 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.8
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.64		Gain of catalytic residue at V145 (P = 0)
MVP		0.39
MPC		0.47
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.94
Mutation Taster		=63/37	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: rs755502855; hg19: chr13-99907706;