chr11-64287004-A-G

Position:

• chr11-64287004-A-G

Variant summary

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

The NM_001170880.2(GPR137):​c.397A>G​(p.Ser133Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPR137 NM_001170880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04

Genes affected

GPR137 (HGNC:24300): (G protein-coupled receptor 137) Predicted to be involved in several processes, including negative regulation of bone resorption; negative regulation of osteoclast differentiation; and 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=0.20701271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR137	NM_001170880.2	c.397A>G	p.Ser133Gly	missense_variant	2/7	ENST00000438980.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR137	ENST00000438980.7	c.397A>G	p.Ser133Gly	missense_variant	2/7	1	NM_001170880.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.571A>G (p.S191G) alteration is located in exon 4 (coding exon 4) of the GPR137 gene. This alteration results from a A to G substitution at nucleotide position 571, causing the serine (S) at amino acid position 191 to be replaced by a glycine (G). 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	0.087
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	-0.035
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T;T;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.72	N;N;N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	N;N;N;D;N;N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.44	T;T;T;D;T;T;T;T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;D;T;T;T;T;T;T;T;T
Polyphen		0.18	B;.;.;.;.;B;B;.;P;P;.;.
Vest4		0.54, 0.51, 0.55, 0.54, 0.51
MutPred		0.18		.;.;Gain of methylation at R134 (P = 0.0382);.;Gain of methylation at R134 (P = 0.0382);Gain of methylation at R134 (P = 0.0382);Gain of methylation at R134 (P = 0.0382);Gain of methylation at R134 (P = 0.0382);Gain of methylation at R134 (P = 0.0382);Gain of methylation at R134 (P = 0.0382);Gain of methylation at R134 (P = 0.0382);Gain of methylation at R134 (P = 0.0382);
MVP		0.48
MPC		1.2
ClinPred		0.76	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2034161130; hg19: chr11-64054476;