rs751447996

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_144672.4(OTOA):c.828delT(p.Ser277ValfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000195 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

OTOA
NM_144672.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.79

Publications

3 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 16-21697861-AT-A is Pathogenic according to our data. Variant chr16-21697861-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOA	NM_144672.4 link	c.828delT	p.Ser277ValfsTer3	frameshift_variant	Exon 10 of 29	ENST00000646100.2	NP_653273.3	Q05BM7
OTOA	NM_001161683.2 link	c.591delT	p.Ser198ValfsTer3	frameshift_variant	Exon 5 of 24		NP_001155155.1	Q7RTW8-4Q05BM7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOA	ENST00000646100.2 link	c.828delT	p.Ser277ValfsTer3	frameshift_variant	Exon 10 of 29		NM_144672.4	ENSP00000496564.2		Q7RTW8-5

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000875

AC:

AN:

251326

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000207

AC:

303

AN:

1461550

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

131

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000262

AC:

291

AN:

1111758

Other (OTH)

AF:

0.0000663

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000831

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ser277Valfs*3) in the OTOA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOA are known to be pathogenic (PMID: 11972037). This variant is present in population databases (rs751447996, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of OTOA-related conditions (PMID: 26969326, 33879512). This variant is also known as c.591delT. ClinVar contains an entry for this variant (Variation ID: 402235). For these reasons, this variant has been classified as Pathogenic. -

Mar 27, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33879512, 24963352, 26969326, 27068579) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOA: PVS1, PM3, PM2:Supporting -

Autosomal recessive nonsyndromic hearing loss 22

Pathogenic:2

Dec 03, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.828delT (p.Ser277Valfs*3) frameshift variant in the OTOA gene is predicted to cause a protein termination in exon 9 (out of a total of 28 exons in the coding sequence). Frameshift variants as well as splice-site variants, missense variants, and whole gene deletions have been reported in this gene for affected individuals. In vivo studies have also demonstrated loss of function is likely a mechanism for disease (Lukashkin et al., 2012). This variant is reported at low frequency within the control population databases (Exome Sequencing Project [ESP] = NA, 1000 Genomes = NA, and ExAC = 0.013). In silico algorithms predict the variant is within a conserved region (GERP = 5.77). Therefore, this collective evidence supports the classification of the c.828delT (p.Ser277Valfs*3) as an autosomal recessive Likely Pathogenic variant for Deafness and Hearing loss. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Deafness, autosomal recessive 22 (MIM#607039 ). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 23 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least four probands with hearing loss is and classified as likely pathogenic and pathogenic by diagnostic laboratories in Clinvar (PMID: 24963352, 27068579). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

OTOA-related disorder

Pathogenic:1

Mar 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The OTOA c.828delT variant is predicted to result in a frameshift and premature protein termination (p.Ser277Valfs*3). This variant has been reported as pathogenic in patients with non-syndromic hearing loss (described as c.590delT, Table S2, Shearer et al. 2014. PubMed ID: 24963352; described as c.591delT, Table S3, Sloan-Heggen et al. 2016. PubMed ID: 26969326). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in OTOA are expected to be pathogenic. This variant is interpreted as pathogenic. -

Rare genetic deafness

Pathogenic:1

May 05, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser277fs variant in OTOA has not been previously reported in individuals w ith hearing loss. This variant has been identified in 9/66700 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs751447996); however, its frequency is low enough to be consistent with a r ecessive carrier frequency. This variant is predicted to cause a frameshift, whi ch alters the protein?s amino acid sequence beginning at position 277 and leads to a premature termination codon 3 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Loss of function of the O TOA gene is an established disease mechanism in autosomal recessive sensorineura l hearing loss. In summary, this variant meets our criteria to be classified as pathogenic for sensorineural hearing loss in an autosomal recessive manner based on the predicted impact of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.8

Mutation Taster

=0/200

disease causing (ClinVar)

(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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rs751447996

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