14-52553560-C-A

Variant names:

• chr14-52553560-C-A
• rs372313581
• NM_001099652.2:c.413C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001099652.2(GPR137C):​c.413C>A​(p.Thr138Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T138M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GPR137C NM_001099652.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

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.413C>A	p.Thr138Lys	missense	Exon 1 of 7	NP_001093122.1	Q8N3F9
	GPR137C	NM_001353361.2		c.413C>A	p.Thr138Lys	missense	Exon 1 of 8	NP_001340290.1
	GPR137C	NR_148417.2		n.725C>A		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.413C>A	p.Thr138Lys	missense	Exon 1 of 7	ENSP00000315106.6	Q8N3F9
	GPR137C	ENST00000542169.6	TSL:1	c.272C>A	p.Thr91Lys	missense	Exon 1 of 8	ENSP00000439165.2	H0YFL6
	TXNDC16	ENST00000936707.1		c.-399G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 21	ENSP00000606766.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452736 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 722612

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 43680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39410

South Asian (SAS) AF: 0.00 AC: 0 AN: 85298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109398

Other (OTH) AF: 0.00 AC: 0 AN: 60192

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	30
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.78
MutPred		0.75		Gain of ubiquitination at T138 (P = 0.0238)
MVP		0.12
MPC		0.82
ClinPred		0.99	D
GERP RS		3.0
PromoterAI		0.0062	Neutral
Varity_R		0.63
gMVP		0.87
Mutation Taster		=56/44	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: rs372313581; hg19: chr14-53020278;