rs464691

Positions:

Variant summary

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

The NM_144672.4(OTOA):c.2417A>C(p.Tyr806Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,613,148 control chromosomes in the GnomAD database, including 2 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 (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

OTOA
NM_144672.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: -0.357

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=0.007861853).

BP6

Variant 16-21736376-A-C is Benign according to our data. Variant chr16-21736376-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 227749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-21736376-A-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 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.2417A>C	p.Tyr806Ser	missense_variant	22/29	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.2417A>C	p.Tyr806Ser	missense_variant	22/29		NM_144672.4	ENSP00000496564.2		Q7RTW8-5

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

194

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000422

AC:

106

AN:

250996

Hom.:

AF XY:

0.000398

AC XY:

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.00279

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000998

Gnomad EAS exome

AF:

0.000602

Gnomad SAS exome

AF:

0.000851

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000252

AC:

368

AN:

1461070

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

178

AN XY:

726818

show subpopulations

Gnomad4 AFR exome

AF:

0.00303

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000505

Gnomad4 SAS exome

AF:

0.000731

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.00127

AC:

193

AN:

152078

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00391

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000692

Hom.:

Bravo

AF:

0.00141

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000815

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2018	- -

OTOA-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

The OTOA c.2417A>C variant is predicted to result in the amino acid substitution p.Tyr806Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.35% of alleles in individuals of African descent in gnomAD. Although we suspect that 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 08, 2015

p.Tyr806Ser in exon 21 of OTOA: This variant is not expected to have clinical s ignificance because the tyrosine (Tyr) residue at position 806 is not conserved through species, with >10 mammals having a serine (Ser) at this position. It has been identified in 0.4% (41/10356) of African chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs464691). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.13

DANN

Benign

0.49

DEOGEN2

Benign

0.0093

.;T;.;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.16

.;T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0079

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.3

.;N;.;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

1.4

.;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.42

.;T;T;T;T

Sift4G

Benign

0.51

.;T;T;T;T

Polyphen

0.0

.;B;.;.;B

Vest4

0.022, 0.023, 0.021

MVP

0.14

MPC

0.24

ClinPred

0.0055

GERP RS

-1.7

Varity_R

0.048

gMVP

0.19

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