rs751447996
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_144672.4(OTOA):βc.828delTβ(p.Ser277fs) 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 (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000072 ( 0 hom., cov: 32)
Exomes π: 0.00021 ( 0 hom. )
Consequence
OTOA
NM_144672.4 frameshift
NM_144672.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.79
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]
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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
Ensembl
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GnomAD3 genomes 0.0000723 AC: 11AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251326Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135824
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GnomAD4 exome AF: 0.000207 AC: 303AN: 1461550Hom.: 0 Cov.: 31 AF XY: 0.000180 AC XY: 131AN XY: 727104
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GnomAD4 genome 0.0000723 AC: 11AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74324
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 23, 2024 | 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) - |
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.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. - |
| 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, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 28, 2024 | 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
| 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. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at