rs727505157
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_194248.3(OTOF):βc.2977_2978delβ(p.Gln994ValfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000373 in 1,608,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000034 ( 0 hom. )
Consequence
OTOF
NM_194248.3 frameshift
NM_194248.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.12
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 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 2-26475926-ACT-A is Pathogenic according to our data. Variant chr2-26475926-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 179828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.2977_2978del | p.Gln994ValfsTer7 | frameshift_variant | 24/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.736_737del | p.Gln247ValfsTer7 | frameshift_variant | 7/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.2977_2978del | p.Gln994ValfsTer7 | frameshift_variant | 24/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.736_737del | p.Gln247ValfsTer7 | frameshift_variant | 7/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151672Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000413 AC: 1AN: 242054Hom.: 0 AF XY: 0.00000761 AC XY: 1AN XY: 131430
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1456618Hom.: 0 AF XY: 0.00000690 AC XY: 5AN XY: 724198
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GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151672Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74082
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2023 | This sequence change creates a premature translational stop signal (p.Gln994Valfs*7) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is present in population databases (rs727505157, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with temperature sensitive non-syndromic auditory neuropathy (PMID: 20504331). This variant is also known as c.2975_2978delAG (p.Q994VfsX6) . ClinVar contains an entry for this variant (Variation ID: 179828). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2022 | 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33426078, 20504331) - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 10, 2014 | The Gln994fs variant in OTOF has been reported in one Chinese individual with te mperature sensitive non-syndromic auditory neuropathy (Wang 2010) who was compou nd heterozygous with a second OTOF variant. The Gln994fs variant has not been id entified in large population studies. This variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 994 and leads to a premature termination codon 7 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. In summary, thi s variant meets our criteria to be classified as pathogenic (www.partners.org/pe rsonalizedmedicine/lmm). - |
Autosomal recessive nonsyndromic hearing loss 9 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at