Variant chr17-74941641-A-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001272005.2(OTOP3):c.268A>T(p.Ser90Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

OTOP3
NM_001272005.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54

Variant links:

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]

OTOP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
OTOP3	NM_001272005.2 linkuse as main transcript	c.268A>T	p.Ser90Cys	missense_variant	2/7	ENST00000328801.6
OTOP3	NM_178233.2 linkuse as main transcript	c.322A>T	p.Ser108Cys	missense_variant	2/7
OTOP3	XM_011524744.3 linkuse as main transcript	c.235A>T	p.Ser79Cys	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOP3	ENST00000328801.6 linkuse as main transcript	c.268A>T	p.Ser90Cys	missense_variant	2/7	2	NM_001272005.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250998

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727226

show subpopulations

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:

0.0000647

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.322A>T (p.S108C) alteration is located in exon 2 (coding exon 2) of the OTOP3 gene. This alteration results from a A to T substitution at nucleotide position 322, causing the serine (S) at amino acid position 108 to be replaced by a cysteine (C). 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

0.17

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.64

REVEL

Uncertain

0.35

Polyphen

1.0

.;D

MVP

0.50

MPC

0.21

ClinPred

0.95

GERP RS

4.9

Varity_R

0.21

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over