chr2-26519100-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7
The NM_194248.3(OTOF):c.237G>A(p.Gly79=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,597,790 control chromosomes in the GnomAD database, including 4 homozygotes. 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 0.00062 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00046 ( 4 hom. )
Consequence
OTOF
NM_194248.3 synonymous
NM_194248.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.477
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 -4 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP6
?
Variant 2-26519100-C-T is Benign according to our data. Variant chr2-26519100-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48195.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
BP7
?
Synonymous conserved (PhyloP=0.477 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.237G>A | p.Gly79= | synonymous_variant | 4/47 | ENST00000272371.7 | |
OTOF | NM_001287489.2 | c.237G>A | p.Gly79= | synonymous_variant | 4/46 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.237G>A | p.Gly79= | synonymous_variant | 4/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000403946.7 | c.237G>A | p.Gly79= | synonymous_variant | 4/46 | 5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000624 AC: 95AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000938 AC: 214AN: 228040Hom.: 1 AF XY: 0.000951 AC XY: 117AN XY: 123012
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GnomAD4 exome AF: 0.000460 AC: 665AN: 1445468Hom.: 4 Cov.: 32 AF XY: 0.000461 AC XY: 331AN XY: 717816
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2021 | This variant is associated with the following publications: (PMID: 20224275) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | OTOF: BP4, BP7 - |
Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | Gly79Gly in Exon 04 of OTOF: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 1/7018 European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs117985483). - |
Computational scores
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BayesDel_noAF
Benign
Cadd
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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