17-74941795-C-G

Position:

• chr17-74941795-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001272005.2(OTOP3):​c.422C>G​(p.Pro141Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: OTOP3 NM_001272005.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

Genes affected

OTOP3 (HGNC:19658): (otopetrin 3) Predicted to enable proton channel activity. Predicted to be involved in proton transmembrane transport. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOP3	NM_001272005.2	c.422C>G	p.Pro141Arg	missense_variant	2/7	ENST00000328801.6
OTOP3	NM_178233.2	c.476C>G	p.Pro159Arg	missense_variant	2/7
OTOP3	XM_011524744.3	c.389C>G	p.Pro130Arg	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOP3	ENST00000328801.6	c.422C>G	p.Pro141Arg	missense_variant	2/7	2	NM_001272005.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 73

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

Jun 05, 2023

The c.476C>G (p.P159R) alteration is located in exon 2 (coding exon 2) of the OTOP3 gene. This alteration results from a C to G substitution at nucleotide position 476, causing the proline (P) at amino acid position 159 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	Benign	0.26
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	.;M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.54	T
REVEL	Benign	0.18
Polyphen		1.0	.;D
MutPred		0.88		.;Gain of methylation at P159 (P = 0.0208);
MVP		0.46
MPC		0.18
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.30
gMVP		0.65

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: rs2039177717; hg19: chr17-72937890;