15-39801955-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007223.3(GPR176):c.725T>C(p.Ile242Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GPR176 NM_007223.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

GPR176 (HGNC:32370): (G protein-coupled receptor 176) Members of the G protein-coupled receptor family, such as GPR176, are cell surface receptors involved in responses to hormones, growth factors, and neurotransmitters (Hata et al., 1995 [PubMed 7893747]).[supplied by OMIM, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR176	NM_007223.3	c.725T>C	p.Ile242Thr	missense_variant	3/3	ENST00000561100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR176	ENST00000561100.2	c.725T>C	p.Ile242Thr	missense_variant	3/3	1	NM_007223.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 32

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

May 03, 2023

The c.725T>C (p.I242T) alteration is located in exon 3 (coding exon 3) of the GPR176 gene. This alteration results from a T to C substitution at nucleotide position 725, causing the isoleucine (I) at amino acid position 242 to be replaced by a threonine (T). 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	0.95
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.54	N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.13	T;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.53
MutPred		0.61		.;Gain of disorder (P = 0.0247);.;
MVP		0.92
MPC		1.4
ClinPred		0.75	D
GERP RS		5.9
Varity_R		0.13
gMVP		0.77

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: rs1898903897; hg19: chr15-40094156;