rs751127167
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001292063.2(OTOG):βc.499delβ(p.Val167TrpfsTer53) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,458,130 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 0.00034 ( 0 hom., cov: 33)
Exomes π: 0.000033 ( 0 hom. )
Consequence
OTOG
NM_001292063.2 frameshift
NM_001292063.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.08
Genes affected
OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]
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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
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Very rare variant in population databases, with high coverage;
PP5
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Variant 11-17553476-TG-T is Pathogenic according to our data. Variant chr11-17553476-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.499del | p.Val167TrpfsTer53 | frameshift_variant | 6/56 | ENST00000399397.6 | |
OTOG | NM_001277269.2 | c.535del | p.Val179TrpfsTer53 | frameshift_variant | 5/55 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.499del | p.Val167TrpfsTer53 | frameshift_variant | 6/56 | 5 | NM_001292063.2 | P2 | |
OTOG | ENST00000399391.7 | c.535del | p.Val179TrpfsTer53 | frameshift_variant | 5/55 | 5 | A2 | ||
OTOG | ENST00000498332.5 | n.405del | non_coding_transcript_exon_variant | 5/16 | 5 | ||||
OTOG | ENST00000428619.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000335 AC: 51AN: 152178Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000103 AC: 8AN: 77876Hom.: 0 AF XY: 0.0000764 AC XY: 3AN XY: 39242
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GnomAD4 exome AF: 0.0000329 AC: 43AN: 1305952Hom.: 0 Cov.: 32 AF XY: 0.0000237 AC XY: 15AN XY: 634020
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GnomAD4 genome ? AF: 0.000335 AC: 51AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24AN XY: 74342
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change creates a premature translational stop signal (p.Val179Trpfs*53) in the OTOG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). This variant is present in population databases (rs751127167, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 228284). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 23, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2023 | 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; Identified as a heterozygous variant in an unaffected member of a Brazilian cohort in published literature (Quaio et al., 2022); This variant is associated with the following publications: (PMID: 36147510) - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 04, 2016 | The p.Val179fs variant in OTOG has not been previously reported in individuals w ith hearing loss. This variant has been identified in 1/722 of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org); h owever, this frequency is low enough to be consistent with a recessive carrier f requency. This variant is predicted to cause a frameshift, which alters the prot ein?s amino acid sequence beginning at position 179 and leads to a premature ter mination codon 53 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Two loss of function variants in the OTOG gene have been reported to segregate with hearing loss in two families (Schrader s 2012), and disruption of Otog in mice resulted in deafness supporting of a los s-of-function mechanism for the disease (Simmler 2000). While these two studies provide evidence of a causative link between loss of function of OTOG and autoso mal recessive hearing loss, to date, no other publications report on OTOG varian ts in individuals with hearing loss. In summary, although additional evidence is required to strengthen the gene-disease association for OTOG and hearing loss, the current data supports a likely pathogenic role for the p.Val179fs variant. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at