rs464696

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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. 14/20 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 0.0093 ( 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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 id is 218840.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}. Variant chr16-21736312-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOA	NM_144672.4 linkuse as main transcript	c.2353A>C	p.Thr785Pro	missense_variant	22/29	ENST00000646100.2	NP_653273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2 linkuse as main transcript	c.2353A>C	p.Thr785Pro	missense_variant	22/29		NM_144672.4	ENSP00000496564	P2	Q7RTW8-5

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

GnomAD4 exome

AF:

0.00271

AC:

3856

AN:

1421226

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

1885

AN XY:

707592

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.0153

Gnomad4 ASJ exome

AF:

0.000506

Gnomad4 EAS exome

AF:

0.109

Gnomad4 SAS exome

AF:

0.000240

Gnomad4 FIN exome

AF:

0.00516

Gnomad4 NFE exome

AF:

0.000216

Gnomad4 OTH exome

AF:

0.00259

GnomAD4 genome

AF:

0.00928

AC:

1360

AN:

146628

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

769

AN XY:

71166

show subpopulations

Gnomad4 AFR

AF:

0.00158

Gnomad4 AMR

AF:

0.0358

Gnomad4 ASJ

AF:

0.00177

Gnomad4 EAS

AF:

0.112

Gnomad4 SAS

AF:

0.0105

Gnomad4 FIN

AF:

0.0247

Gnomad4 NFE

AF:

0.00138

Gnomad4 OTH

AF:

0.0130

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 04, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 31, 2015	- -

OTOA-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

DANN

Benign

0.095

DEOGEN2

Benign

0.012

.;T;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00036

LIST_S2

Benign

0.20

.;T;T;T;T

MetaRNN

Benign

0.0034

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.6

.;N;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

2.2

.;N;N;N;N

REVEL

Benign

0.069

Sift

Benign

1.0

.;T;T;T;T

Sift4G

Benign

1.0

.;T;T;T;T

Polyphen

0.0

.;B;.;.;B

Vest4

0.11, 0.11, 0.13, 0.11

MVP

0.22

MPC

0.22

ClinPred

0.011

GERP RS

4.2

Varity_R

0.11

gMVP

0.30

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