rs145689709

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001292063.2(OTOG):c.4022G>A(p.Arg1341Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00349 in 1,550,594 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1341W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 16 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.07

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006433457).

BP6

Variant 11-17606001-G-A is Benign according to our data. Variant chr11-17606001-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226891.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr11-17606001-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.4022G>A	p.Arg1341Gln	missense_variant	33/56	ENST00000399397.6
OTOG	NM_001277269.2 linkuse as main transcript	c.4058G>A	p.Arg1353Gln	missense_variant	32/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.4022G>A	p.Arg1341Gln	missense_variant	33/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.4058G>A	p.Arg1353Gln	missense_variant	32/55	5		A2	Q6ZRI0-1
OTOG	ENST00000342528.2 linkuse as main transcript	n.1360G>A		non_coding_transcript_exon_variant	9/22	2

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

433

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00461

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00242

AC:

360

AN:

148718

Hom.:

AF XY:

0.00255

AC XY:

204

AN XY:

80130

show subpopulations

Gnomad AFR exome

AF:

0.000443

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00406

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000488

Gnomad FIN exome

AF:

0.000302

Gnomad NFE exome

AF:

0.00408

Gnomad OTH exome

AF:

0.00674

GnomAD4 exome

AF:

0.00356

AC:

4974

AN:

1398248

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

2379

AN XY:

689654

show subpopulations

Gnomad4 AFR exome

AF:

0.000918

Gnomad4 AMR exome

AF:

0.00210

Gnomad4 ASJ exome

AF:

0.00429

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.000442

Gnomad4 FIN exome

AF:

0.000208

Gnomad4 NFE exome

AF:

0.00410

Gnomad4 OTH exome

AF:

0.00428

GnomAD4 genome

AF:

0.00283

AC:

431

AN:

152346

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00459

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00297

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00415

AC:

ExAC

AF:

0.00141

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	OTOG: BP4, BS2 -

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

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 24, 2015

p.Arg1353Gln in exon 32 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 0.56% (29/5214) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145689709). -

OTOG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2020

This variant is classified as likely 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

0.080

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

0.97

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

0.78

N;.

REVEL

Benign

0.12

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.0050

D;D

Vest4

0.16

MVP

0.11

ClinPred

0.047

GERP RS

3.1

Varity_R

0.14

gMVP

0.69

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