chr13-99255314-G-T

Position:

• chr13-99255314-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001098200.2(GPR18):​c.559C>A​(p.Leu187Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,614,134 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (18 hom.)
• Consequence: GPR18 NM_001098200.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.246

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011510104).
• BP6: Variant 13-99255314-G-T is Benign according to our data. Variant chr13-99255314-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 770422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR18	NM_001098200.2	c.559C>A	p.Leu187Met	missense_variant	2/2	ENST00000397470.5
UBAC2	NM_001144072.2	c.389+10690G>T		intron_variant		ENST00000403766.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR18	ENST00000397470.5	c.559C>A	p.Leu187Met	missense_variant	2/2	1	NM_001098200.2	P1
UBAC2	ENST00000403766.8	c.389+10690G>T		intron_variant		2	NM_001144072.2	P1

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 458 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00311 AC: 780 AN: 251134 Hom.: 0 AF XY: 0.00317 AC XY: 430 AN XY: 135708

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00558

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00488 AC: 7127 AN: 1461880 Hom.: 18 Cov.: 33 AF XY: 0.00478 AC XY: 3478 AN XY: 727240

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.00592

Gnomad4 OTH exome AF: 0.00334

GnomAD4 genome AF: 0.00301 AC: 458 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00282 AC XY: 210 AN XY: 74460

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00537

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00482 Hom.: 7

Bravo AF: 0.00324

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00320 AC: 389

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00528

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.0
DANN	Benign	0.97
DEOGEN2	Benign	0.028	T;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	.;T;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.28	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.14	T;T;T
Sift4G	Uncertain	0.044	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.39
MVP		0.22
MPC		0.33
ClinPred		0.016	T
GERP RS		0.60
Varity_R		0.073
gMVP		0.50

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: rs41279138; hg19: chr13-99907568;