rs147355325

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001292063.2(OTOG):c.1397T>G(p.Phe466Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000384 in 1,550,706 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.67

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073337257).

BP6

Variant 11-17560763-T-G is Benign according to our data. Variant chr11-17560763-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 227765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0021 (319/152258) while in subpopulation AFR AF= 0.00693 (288/41542). AF 95% confidence interval is 0.00627. There are 3 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.1397T>G	p.Phe466Cys	missense_variant	Exon 13 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.1433T>G	p.Phe478Cys	missense_variant	Exon 12 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.1397T>G	p.Phe466Cys	missense_variant	Exon 13 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.1433T>G	p.Phe478Cys	missense_variant	Exon 12 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000498332.5 link	n.1303T>G		non_coding_transcript_exon_variant	Exon 12 of 16	5

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00693

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.000478

GnomAD3 exomes

AF:

0.000393

AC:

AN:

150022

Hom.:

AF XY:

0.000310

AC XY:

AN XY:

80664

show subpopulations

Gnomad AFR exome

AF:

0.00712

Gnomad AMR exome

AF:

0.000326

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:

0.00

Gnomad OTH exome

AF:

0.000459

GnomAD4 exome

AF:

0.000198

AC:

277

AN:

1398448

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

129

AN XY:

689758

show subpopulations

Gnomad4 AFR exome

AF:

0.00598

Gnomad4 AMR exome

AF:

0.000616

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:

0.0000213

Gnomad4 OTH exome

AF:

0.000655

GnomAD4 genome

AF:

0.00210

AC:

319

AN:

152258

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00693

Gnomad4 AMR

AF:

0.00150

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:

0.000473

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.00249

ExAC

AF:

0.000251

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 11, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Jun 22, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Phe478Cys in exon 12 of OTOG: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (108/15306) of African chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs147355325). -

OTOG-related disorder

Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Pathogenic

0.85

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.0073

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.4

D;.

REVEL

Benign

0.22

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.0090

D;D

Vest4

0.56

MVP

0.45

ClinPred

0.052

GERP RS

5.0

Varity_R

0.29

gMVP

0.77

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