Genetic Variant GPR137C:p.Ala15Ser (chr14-52553190-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001099652.2(GPR137C):c.43G>T(p.Ala15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000431 in 1,205,390 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: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

GPR137C
NM_001099652.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.114

Variant links:

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]

GPR137C links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034783244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR137C	NM_001099652.2 link	c.43G>T	p.Ala15Ser	missense_variant	Exon 1 of 7	ENST00000321662.11	NP_001093122.1	Q8N3F9B3KW22Q6AWC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GPR137C	ENST00000321662.11 link	c.43G>T	p.Ala15Ser	missense_variant	Exon 1 of 7	1	NM_001099652.2	ENSP00000315106.6	Q8N3F9
GPR137C	ENST00000542169.6 link	c.-99G>T		upstream_gene_variant		1		ENSP00000439165.2	H0YFL6
GPR137C	ENST00000555622.1 link	c.-231G>T		upstream_gene_variant		3		ENSP00000452563.1	H0YJZ7

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

151086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000388

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000323

AC:

AN:

1054194

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

497830

show subpopulations

Gnomad4 AFR exome

AF:

0.000876

Gnomad4 AMR exome

AF:

0.000269

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:

0.00

Gnomad4 OTH exome

AF:

0.000313

GnomAD4 genome

AF:

0.000119

AC:

AN:

151196

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

AN XY:

73878

show subpopulations

Gnomad4 AFR

AF:

0.000435

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000117

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.43G>T (p.A15S) alteration is located in exon 1 (coding exon 1) of the GPR137C gene. This alteration results from a G to T substitution at nucleotide position 43, causing the alanine (A) at amino acid position 15 to be replaced by a serine (S). 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

0.089

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.0031

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.34

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.14

REVEL

Benign

0.035

Sift

Benign

0.69

Sift4G

Benign

0.91

Polyphen

0.050

Vest4

0.13

MutPred

0.14

Gain of glycosylation at A15 (P = 0.0012);

MVP

0.20

MPC

1.3

ClinPred

0.056

GERP RS

0.25

Varity_R

0.042

gMVP

0.19

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