rs464696

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_144672.4(OTOA):c.2353A>C(p.Thr785Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,567,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 0 hom. )

Consequence

OTOA
NM_144672.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.17

Publications

17 publications found

Variant links:

Genes affected

OTOA (HGNC:16378): (otoancorin) The protein encoded by this gene is specifically expressed in the inner ear, and is located at the interface between the apical surface of the inner ear sensory epithelia and their overlying acellular gels. It is prposed that this protein is involved in the attachment of the inner ear acellular gels to the apical surface of the underlying nonsensory cells. Mutations in this gene are associated with autosomal recessive deafness type 22 (DFNB22). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

OTOA Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 22
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Variant has high frequency in the EAS (0.106) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 0).

BP4

Computational evidence support a benign effect (MetaRNN=0.0033976436).

BP6

Variant 16-21736312-A-C is Benign according to our data. Variant chr16-21736312-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218840.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4 link	c.2353A>C	p.Thr785Pro	missense_variant	Exon 22 of 29	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2 link	c.2353A>C	p.Thr785Pro	missense_variant	Exon 22 of 29		NM_144672.4	ENSP00000496564.2

Frequencies

GnomAD3 genomes

AF:

0.00920

AC:

1348

AN:

146512

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00158

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0355

Gnomad ASJ

AF:

0.00177

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.0107

Gnomad FIN

AF:

0.0247

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.000528

AC:

129

AN:

244372

AF XY:

0.000423

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00284

GnomAD4 exome

AF:

0.00271

AC:

3856

AN:

1421226

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

1885

AN XY:

707592

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000180

AC:

AN:

33346

American (AMR)

AF:

0.0153

AC:

532

AN:

34816

Ashkenazi Jewish (ASJ)

AF:

0.000506

AC:

AN:

25680

East Asian (EAS)

AF:

0.109

AC:

2644

AN:

24186

South Asian (SAS)

AF:

0.000240

AC:

AN:

83236

European-Finnish (FIN)

AF:

0.00516

AC:

250

AN:

48444

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.000216

AC:

239

AN:

1107898

Other (OTH)

AF:

0.00259

AC:

150

AN:

57928

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

476

952

1429

1905

2381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.00928

AC:

1360

AN:

146628

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

769

AN XY:

71166

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00158

AC:

AN:

41230

American (AMR)

AF:

0.0358

AC:

481

AN:

13434

Ashkenazi Jewish (ASJ)

AF:

0.00177

AC:

AN:

3398

East Asian (EAS)

AF:

0.112

AC:

404

AN:

3598

South Asian (SAS)

AF:

0.0105

AC:

AN:

4574

European-Finnish (FIN)

AF:

0.0247

AC:

237

AN:

9608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

67582

Other (OTH)

AF:

0.0130

AC:

AN:

2000

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

166

333

499

666

832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00442

Hom.:

ExAC

AF:

0.00226

AC:

274

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jan 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr785Pro variant in OTOA is classified as benign because it has been iden tified in 0.9% (139/15388) of East Asian chromosomes by gnomAD (http://gnomad.br oadinstitute.org). Furthermore, the threonine (Thr) at this position is not cons erved across species. Over 10 mammals carry a proline (Pro) at this position.

Oct 31, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOA-related disorder

Uncertain:1

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The OTOA c.2353A>C variant is predicted to result in the amino acid substitution p.Thr785Pro. This variant was reported along with a second potentially pathogenic variant in four individuals with auditory neuropathy and was classified as uncertain (Table S8, Song et al. 2021. PubMed ID: 34175691). This variant is reported in 0.84% of alleles in individuals of East Asian descent in gnomAD. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Autosomal recessive nonsyndromic hearing loss 22

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.095

DEOGEN2

Benign

0.0

.;T;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00036

LIST_S2

Benign

0.0

.;T;T;T;T

MetaRNN

Benign

0.0034

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;.;.;.

PhyloP100

1.2

PrimateAI

Benign

0.41

PROVEAN

Benign

0.0

.;N;N;N;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;T;T;T

Sift4G

Pathogenic

0.0

.;T;T;T;T

Vest4

0.0

ClinPred

0.011

GERP RS

4.2

Varity_R

0.11

gMVP

0.30

Mutation Taster

=93/7

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