rs150415498

Positions:

chr16-21716940-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_144672.4(OTOA):c.1522G>A(p.Val508Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,006 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V508A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 11 hom. )

Consequence

OTOA
NM_144672.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.370

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:

OTOA (HGNC:):

OTOA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005751699).

BP6

Variant 16-21716940-G-A is Benign according to our data. Variant chr16-21716940-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOA	NM_144672.4 linkuse as main transcript	c.1522G>A	p.Val508Met	missense_variant	15/29	ENST00000646100.2	NP_653273.3	Q05BM7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2 linkuse as main transcript	c.1522G>A	p.Val508Met	missense_variant	15/29		NM_144672.4	ENSP00000496564.2		Q7RTW8-5

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00586

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00278

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00218

AC:

547

AN:

251320

Hom.:

AF XY:

0.00218

AC XY:

296

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00540

Gnomad NFE exome

AF:

0.00339

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00220

AC:

3218

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1599

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00558

Gnomad4 NFE exome

AF:

0.00247

Gnomad4 OTH exome

AF:

0.00152

GnomAD4 genome

AF:

0.00188

AC:

286

AN:

152156

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00586

Gnomad4 NFE

AF:

0.00278

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00227

AC:

275

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00245

EpiControl

AF:

0.00225

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	OTOA: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 13, 2017

p.Val508Met in exon 14 of OTOA: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (150/25792) of Finnish and 0.3 3% (423/126554) European chromosomes including 3 homozygotes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs150415498). -

OTOA-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2020

This variant is classified as likely 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

0.089

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.014

.;T;.;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.69

.;T;T;T;T

M_CAP

Benign

0.048

MetaRNN

Benign

0.0058

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.0

.;L;.;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

0.060

.;N;N;N;N

REVEL

Benign

0.063

Sift

Benign

0.19

.;T;T;T;T

Sift4G

Benign

0.20

.;T;T;T;T

Polyphen

0.18, 0.32

.;B;.;.;B

Vest4

0.13, 0.13, 0.12, 0.092

MVP

0.50

MPC

0.18

ClinPred

0.0044

GERP RS

1.8

Varity_R

0.041

gMVP

0.074

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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