Genetic Variant GPR137B:p.Leu129Phe (chr1-236143007-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003272.4(GPR137B):c.385C>T(p.Leu129Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GPR137B
NM_003272.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.78

Variant links:

Genes affected

GPR137B (HGNC:11862): (G protein-coupled receptor 137B) Involved in several processes, including positive regulation of TORC1 signaling; positive regulation of protein localization to lysosome; and regulation of GTPase activity. Located in lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

GPR137B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR137B	NM_003272.4 link	c.385C>T	p.Leu129Phe	missense_variant	Exon 1 of 7	ENST00000366592.8	NP_003263.1	O60478
GPR137B	XM_017002209.3 link	c.385C>T	p.Leu129Phe	missense_variant	Exon 1 of 7		XP_016857698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GPR137B	ENST00000366592.8 link	c.385C>T	p.Leu129Phe	missense_variant	Exon 1 of 7	1	NM_003272.4	ENSP00000355551.3	O60478
GPR137B	ENST00000366591.4 link	n.464C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
GPR137B	ENST00000419162.5 link	n.385C>T		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000401841.2	Q5TAF0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250636

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461264

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.385C>T (p.L129F) alteration is located in exon 1 (coding exon 1) of the GPR137B gene. This alteration results from a C to T substitution at nucleotide position 385, causing the leucine (L) at amino acid position 129 to be replaced by a phenylalanine (F). 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

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.76

MutationAssessor

Uncertain

2.8

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.63

Sift

Benign

0.073

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.50

Gain of catalytic residue at L129 (P = 0.1955);

MVP

0.46

MPC

1.2

ClinPred

0.70

GERP RS

1.4

Varity_R

0.46

gMVP

0.57

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