1-236142891-C-G

Position:

• chr1-236142891-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003272.4(GPR137B):​c.269C>G​(p.Ser90Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GPR137B NM_003272.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35956383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR137B	NM_003272.4	c.269C>G	p.Ser90Cys	missense_variant	1/7	ENST00000366592.8	NP_003263.1
GPR137B	XM_017002209.3	c.269C>G	p.Ser90Cys	missense_variant	1/7		XP_016857698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR137B	ENST00000366592.8	c.269C>G	p.Ser90Cys	missense_variant	1/7	1	NM_003272.4	ENSP00000355551.3
GPR137B	ENST00000366591.4	n.348C>G		non_coding_transcript_exon_variant	1/2	3
GPR137B	ENST00000419162.5	n.269C>G		non_coding_transcript_exon_variant	1/5	5		ENSP00000401841.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Oct 25, 2023

The c.269C>G (p.S90C) alteration is located in exon 1 (coding exon 1) of the GPR137B gene. This alteration results from a C to G substitution at nucleotide position 269, causing the serine (S) at amino acid position 90 to be replaced by a cysteine (C). 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	0.14
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Benign	0.093	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.93	P
Vest4		0.53
MutPred		0.53		Gain of catalytic residue at L91 (P = 0.0517);
MVP		0.41
MPC		1.9
ClinPred		0.91	D
GERP RS		4.0
Varity_R		0.33
gMVP		0.63

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: rs773945482; hg19: chr1-236306191;