14-52553364-C-G

Variant names:

• chr14-52553364-C-G
• rs760894529
• NM_001099652.2:c.217C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099652.2(GPR137C):​c.217C>G​(p.Leu73Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,451,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GPR137C NM_001099652.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

Genes affected

GPR137C (HGNC:25445): (G protein-coupled receptor 137C) Predicted to be involved in positive regulation of TORC1 signaling. Located in lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20819291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR137C	NM_001099652.2	c.217C>G	p.Leu73Val	missense_variant	Exon 1 of 7	ENST00000321662.11	NP_001093122.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR137C	ENST00000321662.11	c.217C>G	p.Leu73Val	missense_variant	Exon 1 of 7	1	NM_001099652.2	ENSP00000315106.6
GPR137C	ENST00000542169.6	c.76C>G	p.Leu26Val	missense_variant	Exon 1 of 8	1		ENSP00000439165.2
GPR137C	ENST00000555622.1	c.-57C>G		upstream_gene_variant		3		ENSP00000452563.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1451990 Hom.: 0 Cov.: 34 AF XY: 0.00000277 AC XY: 2 AN XY: 722664

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217C>G (p.L73V) alteration is located in exon 1 (coding exon 1) of the GPR137C gene. This alteration results from a C to G substitution at nucleotide position 217, causing the leucine (L) at amino acid position 73 to be replaced by a valine (V). 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	0.096
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.064
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.78	P
Vest4		0.26
MutPred		0.31		Gain of loop (P = 0.0051);
MVP		0.13
MPC		1.5
ClinPred		0.35	T
GERP RS		4.5
Varity_R		0.084
gMVP		0.21

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: rs760894529; hg19: chr14-53020082;