3-170084147-T-C

Variant names:

• chr3-170084147-T-C
• rs1225027388
• NM_014373.3:c.175T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014373.3(GPR160):​c.175T>C​(p.Cys59Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000111 in 1,439,662 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: 0.000011 (0 hom.)
• Consequence: GPR160 NM_014373.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83

Genes affected

GPR160 (HGNC:23693): (G protein-coupled receptor 160) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Located in plasma membrane. Part of receptor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR160	NM_014373.3	c.175T>C	p.Cys59Arg	missense_variant	Exon 4 of 4	ENST00000355897.10	NP_055188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR160	ENST00000355897.10	c.175T>C	p.Cys59Arg	missense_variant	Exon 4 of 4	1	NM_014373.3	ENSP00000348161.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1439662 Hom.: 0 Cov.: 28 AF XY: 0.0000140 AC XY: 10 AN XY: 716334

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000145

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.175T>C (p.C59R) alteration is located in exon 4 (coding exon 1) of the GPR160 gene. This alteration results from a T to C substitution at nucleotide position 175, causing the cysteine (C) at amino acid position 59 to be replaced by an arginine (R). 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	0.88
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-11	D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.86
MutPred		0.79		Loss of catalytic residue at S61 (P = 0.0168);Loss of catalytic residue at S61 (P = 0.0168);Loss of catalytic residue at S61 (P = 0.0168);Loss of catalytic residue at S61 (P = 0.0168);
MVP		0.29
MPC		0.62
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.68

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: rs1225027388; hg19: chr3-169801935;