14-52553289-G-C

Variant names:

• chr14-52553289-G-C
• rs934074157
• NM_001099652.2:c.142G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001099652.2(GPR137C):​c.142G>C​(p.Ala48Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000132 in 1,520,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A48S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: GPR137C NM_001099652.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.13
• Publications: 0 publications found

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]

TXNDC16 (HGNC:19965): (thioredoxin domain containing 16) Located in endoplasmic reticulum lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36380488).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099652.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR137C	NM_001099652.2	MANE Select	c.142G>C	p.Ala48Pro	missense	Exon 1 of 7	NP_001093122.1	Q8N3F9
	GPR137C	NM_001353361.2		c.142G>C	p.Ala48Pro	missense	Exon 1 of 8	NP_001340290.1
	GPR137C	NR_148417.2		n.454G>C		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR137C	ENST00000321662.11	TSL:1 MANE Select	c.142G>C	p.Ala48Pro	missense	Exon 1 of 7	ENSP00000315106.6	Q8N3F9
	GPR137C	ENST00000542169.6	TSL:1	c.1G>C	p.Ala1Pro	missense	Exon 1 of 8	ENSP00000439165.2	H0YFL6
	GPR137C	ENST00000866179.1		c.142G>C	p.Ala48Pro	missense	Exon 1 of 6	ENSP00000536238.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1368744 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 673610

African (AFR) AF: 0.00 AC: 0 AN: 30768

American (AMR) AF: 0.00 AC: 0 AN: 34354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24548

East Asian (EAS) AF: 0.00 AC: 0 AN: 34564

South Asian (SAS) AF: 0.00 AC: 0 AN: 76266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4438

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070272

Other (OTH) AF: 0.0000175 AC: 1 AN: 57032

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74222

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T
Eigen	Benign	0.056
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.018	D
Polyphen		0.23	B
Vest4		0.66
MutPred		0.53		Loss of helix (P = 3e-04)
MVP		0.34
MPC		1.8
ClinPred		0.62	D
GERP RS		4.4
PromoterAI		0.020	Neutral
Varity_R		0.64
gMVP		0.81
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs934074157; hg19: chr14-53020007;