NM_001292063.2:c.4012C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001292063.2(OTOG):c.4012C>T(p.Arg1338Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,550,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1338Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1O:1

Conservation

PhyloP100: 0.887

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 18B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0210253).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000729 (111/152338) while in subpopulation AFR AF = 0.00226 (94/41578). AF 95% confidence interval is 0.00189. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.4012C>T	p.Arg1338Trp	missense_variant	Exon 33 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.4048C>T	p.Arg1350Trp	missense_variant	Exon 32 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
OTOG	ENST00000399397.6 link	c.4012C>T	p.Arg1338Trp	missense_variant	Exon 33 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.4048C>T	p.Arg1350Trp	missense_variant	Exon 32 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2 link	n.1350C>T		non_coding_transcript_exon_variant	Exon 9 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.000729

AC:

111

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000222

AC:

AN:

148842

AF XY:

0.000249

show subpopulations

Gnomad AFR exome

AF:

0.00207

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000364

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000192

AC:

268

AN:

1398248

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

122

AN XY:

689648

show subpopulations

African (AFR)

AF:

0.00253

AC:

AN:

31596

American (AMR)

AF:

0.000168

AC:

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000770

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000100

AC:

108

AN:

1078972

Other (OTH)

AF:

0.000224

AC:

AN:

57996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152338

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00226

AC:

AN:

41578

American (AMR)

AF:

0.000588

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000815

Hom.:

Bravo

AF:

0.000744

ExAC

AF:

0.000300

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jan 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1350 of the OTOG protein (p.Arg1350Trp). This variant is present in population databases (rs61734125, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 227777). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

May 06, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal recessive nonsyndromic hearing loss 18B

Uncertain:1Other:1

Nov 02, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 04-26-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not specified

Benign:1

Feb 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg1350Trp in exon 32 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals, sug gesting that variants at this position are tolerated. Of note, 2 mammals (marmos et and Bactrian camel) have a Tryptophan (Trp) at this position. In addition, c omputational prediction tools do not suggest a high likelihood of impact to the protein. The variant has been reported in 1/920 African chromosomes by the Exome Aggregate Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61734125). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

PhyloP100

0.89

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-4.4

D;.

REVEL

Benign

0.058

Sift

Uncertain

0.028

D;.

Sift4G

Uncertain

0.022

D;D

Vest4

0.15

MVP

0.36

ClinPred

0.043

GERP RS

3.2

Varity_R

0.36

gMVP

0.78

Mutation Taster

=77/23

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over