rs150452778
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7
The NM_194248.3(OTOF):c.1530C>T(p.Ile510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000991 in 1,613,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00089 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0010 ( 0 hom. )
Consequence
OTOF
NM_194248.3 synonymous
NM_194248.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.314
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 Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 2-26482455-G-A is Benign according to our data. Variant chr2-26482455-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48173.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr2-26482455-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.314 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| OTOF | NM_194248.3 | c.1530C>T | p.Ile510= | synonymous_variant | 14/47 | ENST00000272371.7 | NP_919224.1 | |
| OTOF | NM_001287489.2 | c.1530C>T | p.Ile510= | synonymous_variant | 14/46 | NP_001274418.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| OTOF | ENST00000272371.7 | c.1530C>T | p.Ile510= | synonymous_variant | 14/47 | 1 | NM_194248.3 | ENSP00000272371 | A1 | |
| OTOF | ENST00000403946.7 | c.1530C>T | p.Ile510= | synonymous_variant | 14/46 | 5 | ENSP00000385255 | P4 |
Frequencies
GnomAD3 genomes 0.000887 AC: 135AN: 152224Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000705 AC: 177AN: 250886Hom.: 0 AF XY: 0.000640 AC XY: 87AN XY: 135856
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GnomAD4 exome AF: 0.00100 AC: 1463AN: 1460978Hom.: 0 Cov.: 32 AF XY: 0.000948 AC XY: 689AN XY: 726776
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GnomAD4 genome 0.000886 AC: 135AN: 152342Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | OTOF: BP4, BP7 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 29, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2021 | - - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 02, 2015 | p.Ile510Ile in exon 14 of OTOF: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (79/65848) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs150452778). - |
OTOF-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 28, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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BayesDel_noAF
Benign
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Benign
DANN
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at