rs76180450
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_ModerateBP6_Very_Strong
The NM_194248.3(OTOF):c.37C>T(p.Leu13=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000332 in 1,614,000 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0019 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00017 ( 1 hom. )
Consequence
OTOF
NM_194248.3 synonymous
NM_194248.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 4.07
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 Benign. Variant got -8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.34).
BP6
?
Variant 2-26558535-G-A is Benign according to our data. Variant chr2-26558535-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48226.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.37C>T | p.Leu13= | synonymous_variant | 1/47 | ENST00000272371.7 | |
OTOF | NM_001287489.2 | c.37C>T | p.Leu13= | synonymous_variant | 1/46 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.37C>T | p.Leu13= | synonymous_variant | 1/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000403946.7 | c.37C>T | p.Leu13= | synonymous_variant | 1/46 | 5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00187 AC: 284AN: 152110Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000501 AC: 126AN: 251324Hom.: 1 AF XY: 0.000265 AC XY: 36AN XY: 135870
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GnomAD4 exome AF: 0.000172 AC: 251AN: 1461772Hom.: 1 Cov.: 31 AF XY: 0.000144 AC XY: 105AN XY: 727200
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GnomAD4 genome ? AF: 0.00187 AC: 285AN: 152228Hom.: 0 Cov.: 31 AF XY: 0.00161 AC XY: 120AN XY: 74428
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 12, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 14, 2012 | Leu13Leu in Exon 01 of OTOF: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence, and has been identified in 0.8% (31/3738) of Afric an American chromosomes from a broad population by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS; dbSNP rs76180450). - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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