rs183470913

Positions:

Variant summary

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

The NM_001292063.2(OTOG):c.7867G>A(p.Asp2623Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00045 in 1,550,386 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 5.52

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005546063).

BP6

Variant 11-17638522-G-A is Benign according to our data. Variant chr11-17638522-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218585.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chr11-17638522-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.7867G>A	p.Asp2623Asn	missense_variant	48/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.7903G>A	p.Asp2635Asn	missense_variant	47/55		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.7867G>A	p.Asp2623Asn	missense_variant	48/56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.7903G>A	p.Asp2635Asn	missense_variant	47/55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 linkuse as main transcript	n.4779G>A		non_coding_transcript_exon_variant	21/22	2

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

348

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00811

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000511

AC:

AN:

148652

Hom.:

AF XY:

0.000375

AC XY:

AN XY:

80060

show subpopulations

Gnomad AFR exome

AF:

0.00914

Gnomad AMR exome

AF:

0.000407

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:

0.0000364

Gnomad OTH exome

AF:

0.000465

GnomAD4 exome

AF:

0.000250

AC:

349

AN:

1398124

Hom.:

Cov.:

AF XY:

0.000225

AC XY:

155

AN XY:

689586

show subpopulations

Gnomad4 AFR exome

AF:

0.00908

Gnomad4 AMR exome

AF:

0.000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000130

Gnomad4 OTH exome

AF:

0.000466

GnomAD4 genome

AF:

0.00229

AC:

349

AN:

152262

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

159

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00811

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.00280

ExAC

AF:

0.000168

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2017	p.Asp2635Asn in exon 47 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 0.85% (130/15230) of African chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs183470913). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	OTOG: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	- -

OTOG-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

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

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.037

T;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0055

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.84

N;.

REVEL

Benign

0.11

Sift

Benign

0.15

T;.

Sift4G

Uncertain

0.011

D;D

Vest4

0.17

MVP

0.15

ClinPred

0.016

GERP RS

5.4

Varity_R

0.10

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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