rs61743165

Positions:

chr11-17634201-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001292063.2(OTOG):c.7400G>A(p.Arg2467His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,550,382 control chromosomes in the GnomAD database, including 1,366 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 118 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1248 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.11

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020101964).

BP6

Variant 11-17634201-G-A is Benign according to our data. Variant chr11-17634201-G-A is described in ClinVar as [Benign]. Clinvar id is 226908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0809 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.7400G>A	p.Arg2467His	missense_variant	44/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.7436G>A	p.Arg2479His	missense_variant	43/55		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.7400G>A	p.Arg2467His	missense_variant	44/56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.7436G>A	p.Arg2479His	missense_variant	43/55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 linkuse as main transcript	n.4605+327G>A		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5627

AN:

152108

Hom.:

118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0376

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0517

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.0873

Gnomad FIN

AF:

0.0345

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0341

Gnomad OTH

AF:

0.0259

GnomAD3 exomes

AF:

0.0405

AC:

5947

AN:

146874

Hom.:

204

AF XY:

0.0426

AC XY:

3371

AN XY:

79208

show subpopulations

Gnomad AFR exome

AF:

0.0334

Gnomad AMR exome

AF:

0.0432

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.00195

Gnomad SAS exome

AF:

0.0866

Gnomad FIN exome

AF:

0.0340

Gnomad NFE exome

AF:

0.0332

Gnomad OTH exome

AF:

0.0342

GnomAD4 exome

AF:

0.0386

AC:

54026

AN:

1398156

Hom.:

1248

Cov.:

AF XY:

0.0399

AC XY:

27491

AN XY:

689606

show subpopulations

Gnomad4 AFR exome

AF:

0.0367

Gnomad4 AMR exome

AF:

0.0418

Gnomad4 ASJ exome

AF:

0.0253

Gnomad4 EAS exome

AF:

0.00151

Gnomad4 SAS exome

AF:

0.0846

Gnomad4 FIN exome

AF:

0.0313

Gnomad4 NFE exome

AF:

0.0375

Gnomad4 OTH exome

AF:

0.0337

GnomAD4 genome

AF:

0.0370

AC:

5636

AN:

152226

Hom.:

118

Cov.:

AF XY:

0.0388

AC XY:

2887

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0375

Gnomad4 AMR

AF:

0.0519

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.0878

Gnomad4 FIN

AF:

0.0345

Gnomad4 NFE

AF:

0.0341

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0342

Hom.:

Bravo

AF:

0.0347

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0374

AC:

144

ExAC

AF:

0.0445

AC:

927

Asia WGS

AF:

0.0640

AC:

223

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg2479His in exon 43 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 4.5% (6/132) of Mexican chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs61743165). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

OTOG-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 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

0.076

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.080

N;.

REVEL

Benign

0.059

Sift

Benign

0.22

T;.

Sift4G

Benign

0.67

T;T

Vest4

0.028

ClinPred

0.0037

GERP RS

2.8

Varity_R

0.041

gMVP

0.39

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