chr11-17570275-C-T

Position:

chr11-17570275-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001292063.2(OTOG):c.1840C>T(p.Arg614Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000342 in 1,550,702 control chromosomes in the GnomAD database, including 1 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 0.00030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 3.74

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02940765).

BP6

Variant 11-17570275-C-T is Benign according to our data. Variant chr11-17570275-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 417901.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.1840C>T	p.Arg614Trp	missense_variant	17/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.1876C>T	p.Arg626Trp	missense_variant	16/55		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.1840C>T	p.Arg614Trp	missense_variant	17/56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.1876C>T	p.Arg626Trp	missense_variant	16/55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000498332.5 linkuse as main transcript	n.1746C>T		non_coding_transcript_exon_variant	16/16	5

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000280

AC:

AN:

150168

Hom.:

AF XY:

0.000273

AC XY:

AN XY:

80680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000444

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000359

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.000348

AC:

486

AN:

1398508

Hom.:

Cov.:

AF XY:

0.000368

AC XY:

254

AN XY:

689762

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.0000840

Gnomad4 ASJ exome

AF:

0.00218

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000382

Gnomad4 OTH exome

AF:

0.000224

GnomAD4 genome

AF:

0.000296

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000589

Hom.:

Bravo

AF:

0.000332

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000464

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 09, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2024	Reported in a patient with sensorineural hearing loss in published literature (PMID: 29907799); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29907799) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 05, 2017

The p.Arg626Trp variant in OTOG has been identified by our laboratory in 2 indiv iduals with hearing loss; however, a variant affecting the other copy of the OTO G gene was not identified in either of them. This variant has been identified in 0.2% (19/8420) of Ashkenazi Jewish chromosomes by the genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201183725). Although it ha s been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summar y, the clinical significance of the p.Arg626Trp variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 18B

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Oct 29, 2015

- -

OTOG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2023

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

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.061

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.3

L;.

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.5

D;.

REVEL

Uncertain

0.38

Sift

Benign

0.076

T;.

Sift4G

Benign

0.21

T;T

Vest4

0.22

MVP

0.59

ClinPred

0.15

GERP RS

3.8

Varity_R

0.19

gMVP

0.64

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