16-21678558-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144672.4(OTOA):c.44T>A(p.Phe15Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 1,613,658 control chromosomes in the GnomAD database, including 4,331 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 492 hom., cov: 31)

Exomes 𝑓: 0.029 ( 3839 hom. )

Consequence

OTOA
NM_144672.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.42

Publications

23 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003518194).

BP6

Variant 16-21678558-T-A is Benign according to our data. Variant chr16-21678558-T-A is described in ClinVar as [Benign]. Clinvar id is 47954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4 link	c.44T>A	p.Phe15Tyr	missense_variant	Exon 2 of 29	ENST00000646100.2	NP_653273.3	Q05BM7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOA	ENST00000646100.2 link	c.44T>A	p.Phe15Tyr	missense_variant	Exon 2 of 29		NM_144672.4	ENSP00000496564.2	Q7RTW8-5
OTOA	ENST00000388958.8 link	c.44T>A	p.Phe15Tyr	missense_variant	Exon 1 of 28	1		ENSP00000373610.3	Q7RTW8-5
OTOA	ENST00000286149.8 link	c.44T>A	p.Phe15Tyr	missense_variant	Exon 1 of 28	5		ENSP00000286149.4	Q7RTW8-1
OTOA	ENST00000647277.1 link	n.44T>A		non_coding_transcript_exon_variant	Exon 2 of 29			ENSP00000495594.1	A0A2R8YG28

Frequencies

GnomAD3 genomes

AF:

0.0511

AC:

7760

AN:

151944

Hom.:

485

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0806

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.0328

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.0506

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00950

Gnomad OTH

AF:

0.0567

GnomAD2 exomes

AF:

0.0681

AC:

17125

AN:

251456

AF XY:

0.0585

show subpopulations

Gnomad AFR exome

AF:

0.0789

Gnomad AMR exome

AF:

0.227

Gnomad ASJ exome

AF:

0.0308

Gnomad EAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0484

GnomAD4 exome

AF:

0.0287

AC:

41897

AN:

1461596

Hom.:

3839

Cov.:

AF XY:

0.0281

AC XY:

20448

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.0787

AC:

2632

AN:

33458

American (AMR)

AF:

0.214

AC:

9582

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

788

AN:

26126

East Asian (EAS)

AF:

0.322

AC:

12734

AN:

39596

South Asian (SAS)

AF:

0.0396

AC:

3417

AN:

86248

European-Finnish (FIN)

AF:

0.0137

AC:

734

AN:

53406

Middle Eastern (MID)

AF:

0.0486

AC:

280

AN:

5766

European-Non Finnish (NFE)

AF:

0.00866

AC:

9629

AN:

1111908

Other (OTH)

AF:

0.0348

AC:

2101

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

1851

3702

5552

7403

9254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0512

AC:

7785

AN:

152062

Hom.:

492

Cov.:

AF XY:

0.0537

AC XY:

3992

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0808

AC:

3351

AN:

41450

American (AMR)

AF:

0.120

AC:

1825

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.0328

AC:

114

AN:

3472

East Asian (EAS)

AF:

0.265

AC:

1363

AN:

5150

South Asian (SAS)

AF:

0.0502

AC:

242

AN:

4818

European-Finnish (FIN)

AF:

0.0109

AC:

116

AN:

10598

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00948

AC:

645

AN:

68012

Other (OTH)

AF:

0.0551

AC:

116

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

339

678

1018

1357

1696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0253

Hom.:

226

Bravo

AF:

0.0658

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.0780

AC:

343

ESP6500EA

AF:

0.0110

AC:

ExAC

AF:

0.0623

AC:

7569

Asia WGS

AF:

0.132

AC:

456

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Phe15Tyr in Exon 01 of OTOA: This variant is not expected to have clinical signi ficance because it has been identified in 8.2% (305/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs78970023). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

.;T;.

Eigen

Benign

-0.085

Eigen_PC

Benign

-0.082

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.46

.;T;T

MetaRNN

Benign

0.0035

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;M;M

PhyloP100

2.4

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.67

.;N;N

REVEL

Benign

0.17

Sift

Benign

0.030

.;D;D

Sift4G

Uncertain

0.042

.;D;D

Vest4

0.12, 0.17

MPC

0.47

ClinPred

0.021

GERP RS

4.7

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.084

gMVP

0.11

Mutation Taster

=95/5

polymorphism (auto)

(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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16-21678558-T-A

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