11-17555877-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001292063.2(OTOG):c.639G>T(p.Glu213Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000551 in 1,551,036 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E213E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0740

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077190697).

BP6

Variant 11-17555877-G-T is Benign according to our data. Variant chr11-17555877-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 227791.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 = 0.0032 (487/152318) while in subpopulation AFR AF = 0.0113 (470/41568). AF 95% confidence interval is 0.0105. There are 2 homozygotes in GnomAd4. There are 236 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.639G>T	p.Glu213Asp	missense_variant	Exon 7 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.675G>T	p.Glu225Asp	missense_variant	Exon 6 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.639G>T	p.Glu213Asp	missense_variant	Exon 7 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.675G>T	p.Glu225Asp	missense_variant	Exon 6 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000485669.1 link	n.178G>T		non_coding_transcript_exon_variant	Exon 1 of 3	4
OTOG	ENST00000498332.5 link	n.545G>T		non_coding_transcript_exon_variant	Exon 6 of 16	5

Frequencies

GnomAD3 genomes

AF:

0.00320

AC:

487

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.0000441

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000556

AC:

AN:

151052

AF XY:

0.000432

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.000284

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000226

GnomAD4 exome

AF:

0.000263

AC:

368

AN:

1398718

Hom.:

Cov.:

AF XY:

0.000244

AC XY:

168

AN XY:

689862

show subpopulations

African (AFR)

AF:

0.0102

AC:

321

AN:

31596

American (AMR)

AF:

0.000364

AC:

AN:

35708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25178

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48406

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1079028

Other (OTH)

AF:

0.000516

AC:

AN:

58130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00320

AC:

487

AN:

152318

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

236

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0113

AC:

470

AN:

41568

American (AMR)

AF:

0.000784

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.00369

ExAC

AF:

0.000454

AC:

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2021

GeneDx

Significance:Likely 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

Jul 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu225Asp in exon 6 of OTOG: This variant is not expected to have clinical sig nificance because it is has been identified in 0.7% (8/1100) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs61736015) and 2.1% (19/908) of African chromosomes from the 1000 Genomes Project . -

OTOG-related disorder

Benign:1

Jun 06, 2024

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

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0077

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

L;.

PhyloP100

-0.074

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.081

Sift

Uncertain

0.027

D;.

Sift4G

Benign

0.15

T;T

Vest4

0.22

MutPred

0.42

Gain of ubiquitination at K224 (P = 0.1162);.;

MVP

0.14

ClinPred

0.041

GERP RS

-3.0

Varity_R

0.097

gMVP

0.36

Mutation Taster

=89/11

polymorphism

(source)

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

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11-17555877-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over