11-17578490-G-T

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.2723G>T(p.Arg908Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,539,486 control chromosomes in the GnomAD database, including 25 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 24 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.92

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=0.0077317357).

BP6

Variant 11-17578490-G-T is Benign according to our data. Variant chr11-17578490-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 226874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17578490-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00345 (526/152348) while in subpopulation NFE AF= 0.00557 (379/68028). AF 95% confidence interval is 0.00511. There are 1 homozygotes in gnomad4. There are 230 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.2723G>T	p.Arg908Leu	missense_variant	Exon 23 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.2759G>T	p.Arg920Leu	missense_variant	Exon 22 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.2723G>T	p.Arg908Leu	missense_variant	Exon 23 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.2759G>T	p.Arg920Leu	missense_variant	Exon 22 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.227G>T		non_coding_transcript_exon_variant	Exon 1 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

526

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00557

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00339

AC:

472

AN:

139106

Hom.:

AF XY:

0.00336

AC XY:

254

AN XY:

75642

show subpopulations

Gnomad AFR exome

AF:

0.00119

Gnomad AMR exome

AF:

0.000449

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000134

Gnomad FIN exome

AF:

0.00183

Gnomad NFE exome

AF:

0.00646

Gnomad OTH exome

AF:

0.00451

GnomAD4 exome

AF:

0.00550

AC:

7631

AN:

1387138

Hom.:

Cov.:

AF XY:

0.00539

AC XY:

3691

AN XY:

684564

show subpopulations

Gnomad4 AFR exome

AF:

0.000728

Gnomad4 AMR exome

AF:

0.000701

Gnomad4 ASJ exome

AF:

0.00751

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000240

Gnomad4 FIN exome

AF:

0.00147

Gnomad4 NFE exome

AF:

0.00649

Gnomad4 OTH exome

AF:

0.00542

GnomAD4 genome

AF:

0.00345

AC:

526

AN:

152348

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.00202

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00557

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00287

Hom.:

Bravo

AF:

0.00343

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00623

AC:

ExAC

AF:

0.00226

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOG: BP4, BS2 -

not specified

Benign:1

Oct 23, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg920Leu in exon 22 of OTOG: This variant is not expected to have clinical si gnificance because it has been identified in 0.6 % (29/4534) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144060182). -

OTOG-related disorder

Benign:1

Nov 11, 2021

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

Benign

0.11

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0077

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.2

N;.

REVEL

Benign

0.079

Sift

Benign

0.29

T;.

Sift4G

Uncertain

0.013

D;D

Vest4

0.24

MVP

0.42

ClinPred

0.014

GERP RS

1.4

Varity_R

0.077

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