chr13-99254885-T-G

Variant names:

• chr13-99254885-T-G
• rs780161923
• NM_001098200.2:c.988A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001098200.2(GPR18):​c.988A>C​(p.Met330Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPR18 NM_001098200.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR18	NM_001098200.2	c.988A>C	p.Met330Leu	missense_variant	Exon 2 of 2	ENST00000397470.5	NP_001091670.1
UBAC2	NM_001144072.2	c.389+10261T>G		intron_variant	Intron 4 of 8	ENST00000403766.8	NP_001137544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR18	ENST00000397470.5	c.988A>C	p.Met330Leu	missense_variant	Exon 2 of 2	1	NM_001098200.2	ENSP00000380610.2
UBAC2	ENST00000403766.8	c.389+10261T>G		intron_variant	Intron 4 of 8	2	NM_001144072.2	ENSP00000383911.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.988A>C (p.M330L) alteration is located in exon 3 (coding exon 1) of the GPR18 gene. This alteration results from a A to C substitution at nucleotide position 988, causing the methionine (M) at amino acid position 330 to be replaced by a leucine (L). 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	0.10
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.41	.;T;.
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.20	N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.66	N;N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.96	D;D;D
Vest4		0.53
MutPred		0.29		Gain of catalytic residue at L331 (P = 0);Gain of catalytic residue at L331 (P = 0);Gain of catalytic residue at L331 (P = 0);
MVP		0.73
MPC		0.078
ClinPred		0.60	D
GERP RS		6.2
Varity_R		0.72
gMVP		0.82

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: rs780161923; hg19: chr13-99907139;