rs397515596
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_194248.3(OTOF):c.2905_2923delinsCTCCGAGCGCA(p.Ala969LeufsTer30) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
OTOF
NM_194248.3 frameshift
NM_194248.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.93
Genes affected
OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 2-26475982-CGGCAAAGAGGCTGCGGGC-TGCGCTCGGAG is Pathogenic according to our data. Variant chr2-26475982-CGGCAAAGAGGCTGCGGGC-TGCGCTCGGAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65794.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.2905_2923delinsCTCCGAGCGCA | p.Ala969LeufsTer30 | frameshift_variant | 24/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.664_682delinsCTCCGAGCGCA | p.Ala222LeufsTer30 | frameshift_variant | 7/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.2905_2923delinsCTCCGAGCGCA | p.Ala969LeufsTer30 | frameshift_variant | 24/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.664_682delinsCTCCGAGCGCA | p.Ala222LeufsTer30 | frameshift_variant | 7/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Bilateral sensorineural hearing impairment Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo | - | The c.2905_2923delinsCTCCGAGCGCA was identified in a Brazilian patient with non-syndromic hearing loss, but a second pathogenic variant could not be detected. Thus its clinical significance is unknown - |
Autosomal recessive nonsyndromic hearing loss 9 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at