rs751447996

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_144672.4(OTOA):c.828del(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:5

Conservation

PhyloP100: 5.79

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

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/exons	MANE	UniProt
OTOA	NM_144672.4 linkuse as main transcript	c.828del	p.Ser277ValfsTer3	frameshift_variant	10/29	ENST00000646100.2
OTOA	NM_001161683.2 linkuse as main transcript	c.591del	p.Ser198ValfsTer3	frameshift_variant	5/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOA	ENST00000646100.2 linkuse as main transcript	c.828del	p.Ser277ValfsTer3	frameshift_variant	10/29		NM_144672.4	P2	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

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251326

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135824

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000262

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 22

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Dec 03, 2015	The c.828delT (p.Ser277Valfs3) 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.Ser277Valfs3) as an autosomal recessive Likely Pathogenic variant for Deafness and Hearing loss. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2023

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 (http://gnomad.broadinstitute.org/variant/16-21709182-AT-A). Frameshift variants in OTOA are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

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. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 05, 2016

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

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