rs61978648

Positions:

chr11-17557227-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001292063.2(OTOG):c.769G>A(p.Val257Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00656 in 1,550,636 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.020 ( 74 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 98 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 3.12

Variant links:

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OTOG links:

OTOG (HGNC:):

OTOG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032092035).

BP6

Variant 11-17557227-G-A is Benign according to our data. Variant chr11-17557227-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226914.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.769G>A	p.Val257Ile	missense_variant	8/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.805G>A	p.Val269Ile	missense_variant	7/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.769G>A	p.Val257Ile	missense_variant	8/56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.805G>A	p.Val269Ile	missense_variant	7/55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000485669.1 linkuse as main transcript	n.308G>A		non_coding_transcript_exon_variant	2/3	4
OTOG	ENST00000498332.5 linkuse as main transcript	n.675G>A		non_coding_transcript_exon_variant	7/16	5

Frequencies

GnomAD3 genomes

AF:

0.0204

AC:

3102

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0568

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0228

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00400

Gnomad OTH

AF:

0.0181

GnomAD3 exomes

AF:

0.00836

AC:

1248

AN:

149234

Hom.:

AF XY:

0.00737

AC XY:

592

AN XY:

80356

show subpopulations

Gnomad AFR exome

AF:

0.0628

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.0161

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00142

Gnomad FIN exome

AF:

0.00101

Gnomad NFE exome

AF:

0.00443

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00505

AC:

7065

AN:

1398332

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

3384

AN XY:

689684

show subpopulations

Gnomad4 AFR exome

AF:

0.0587

Gnomad4 AMR exome

AF:

0.0135

Gnomad4 ASJ exome

AF:

0.0169

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000972

Gnomad4 FIN exome

AF:

0.00129

Gnomad4 NFE exome

AF:

0.00318

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.0204

AC:

3109

AN:

152304

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1474

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0568

Gnomad4 AMR

AF:

0.0228

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.00400

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.0244

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00311

AC:

ExAC

AF:

0.00719

AC:

168

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Val269Ile in exon 7 of OTOG: This variant is not expected to have clinical signi ficance because it has been identified in 7.4% (13/176) of Yoruba (Nigerian) chr omosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nl m.nih.gov/projects/SNP; dbSNP rs61978648). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -

Meniere disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Jan 01, 2020

- -

OTOG-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

0.087

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.090

N;.

REVEL

Benign

0.084

Sift

Benign

0.56

T;.

Sift4G

Benign

0.067

T;T

Vest4

0.16

MVP

0.20

ClinPred

0.011

GERP RS

4.8

Varity_R

0.026

gMVP

0.40

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

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