dbSNP rs464691: OTOA:p.Tyr806Ser (chr16-21736376-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 17/22 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

Publications

1 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=0.007861853).

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 VariationId is 227749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00127 (193/152078) while in subpopulation AFR AF = 0.00391 (162/41388). AF 95% confidence interval is 0.00342. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144672.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOA	NM_144672.4	MANE Select	c.2417A>C	p.Tyr806Ser	missense	Exon 22 of 29	NP_653273.3
OTOA	NM_001161683.2		c.2180A>C	p.Tyr727Ser	missense	Exon 17 of 24	NP_001155155.1
OTOA	NM_170664.3		c.1445A>C	p.Tyr482Ser	missense	Exon 12 of 19	NP_733764.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOA	ENST00000646100.2	MANE Select	c.2417A>C	p.Tyr806Ser	missense	Exon 22 of 29	ENSP00000496564.2
OTOA	ENST00000388958.8	TSL:1	c.2417A>C	p.Tyr806Ser	missense	Exon 21 of 28	ENSP00000373610.3
OTOA	ENST00000286149.8	TSL:5	c.2459A>C	p.Tyr820Ser	missense	Exon 21 of 28	ENSP00000286149.4

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

GnomAD2 exomes

AF:

0.000422

AC:

106

AN:

250996

AF XY:

0.000398

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 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

African (AFR)

AF:

0.00303

AC:

101

AN:

33308

American (AMR)

AF:

0.000112

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.000505

AC:

AN:

39606

South Asian (SAS)

AF:

0.000731

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.000281

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000132

AC:

147

AN:

1111742

Other (OTH)

AF:

0.000265

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00127

AC:

193

AN:

152078

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00391

AC:

162

AN:

41388

American (AMR)

AF:

0.000327

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000578

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68006

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000692

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 12, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOA-related disorder

Uncertain:1

Jan 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jun 08, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.13

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0093

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.16

M_CAP

Benign

0.011

MetaRNN

Benign

0.0079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.3

PhyloP100

-0.36

PrimateAI

Benign

0.32

PROVEAN

Benign

1.4

REVEL

Benign

0.11

Sift

Benign

0.42

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.022

MVP

0.14

MPC

0.24

ClinPred

0.0055

GERP RS

-1.7

Varity_R

0.048

gMVP

0.19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over