11-17609941-G-T

Position:

chr11-17609941-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001292063.2(OTOG):c.4641G>T(p.Glu1547Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000806 in 1,538,114 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00059 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 1 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.141

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011539459).

BP6

Variant 11-17609941-G-T is Benign according to our data. Variant chr11-17609941-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 506169.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr11-17609941-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.4641G>T	p.Glu1547Asp	missense_variant	36/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.4677G>T	p.Glu1559Asp	missense_variant	35/55		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.4641G>T	p.Glu1547Asp	missense_variant	36/56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.4677G>T	p.Glu1559Asp	missense_variant	35/55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 linkuse as main transcript	n.1979G>T		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes

AF:

0.000586

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00112

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000336

AC:

AN:

139704

Hom.:

AF XY:

0.000268

AC XY:

AN XY:

74670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000250

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:

0.000747

Gnomad OTH exome

AF:

0.000738

GnomAD4 exome

AF:

0.000830

AC:

1151

AN:

1386108

Hom.:

Cov.:

AF XY:

0.000795

AC XY:

542

AN XY:

681988

show subpopulations

Gnomad4 AFR exome

AF:

0.0000635

Gnomad4 AMR exome

AF:

0.000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000209

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000905

GnomAD4 genome

AF:

0.000586

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.000566

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000772

Hom.:

Bravo

AF:

0.000563

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.000334

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	OTOG: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 05, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 03, 2017

The p.Glu1559Asp variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 49/62630 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764159927). Although this variant has been seen in the general population, it s frequency is not high enough to rule out a pathogenic role. Computational pred iction tools and conservation analysis suggest that the p.Glu1559Asp variant may not impact the protein, though this information is not predictive enough to rul e out pathogenicity. In summary, the clinical significance of the p.Glu1559Asp v ariant is uncertain. ACMG/AMP Criteria applied: BP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.77

CADD

Benign

8.5

DANN

Benign

0.89

DEOGEN2

Benign

0.048

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.34

N;.

REVEL

Benign

0.021

Sift

Benign

0.25

T;.

Sift4G

Benign

0.26

T;T

Vest4

0.054

MutPred

0.23

Loss of solvent accessibility (P = 0.0509);.;

MVP

0.030

ClinPred

0.033

GERP RS

-1.5

Varity_R

0.046

gMVP

0.32

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