chr2-26480959-G-A
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_194248.3(OTOF):c.1630C>T(p.Arg544Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000749 in 1,609,512 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00090 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00073 ( 2 hom. )
Consequence
OTOF
NM_194248.3 missense
NM_194248.3 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 4.78
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 -5 ACMG points.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000901 (134/148792) while in subpopulation NFE AF= 0.00174 (116/66596). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.1630C>T | p.Arg544Cys | missense_variant | Exon 15 of 47 | 1 | NM_194248.3 | ENSP00000272371.2 | ||
OTOF | ENST00000403946.7 | c.1630C>T | p.Arg544Cys | missense_variant | Exon 15 of 46 | 5 | ENSP00000385255.3 |
Frequencies
GnomAD3 genomes AF: 0.000901 AC: 134AN: 148666Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000769 AC: 192AN: 249668Hom.: 0 AF XY: 0.000797 AC XY: 108AN XY: 135522
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GnomAD4 exome AF: 0.000734 AC: 1072AN: 1460720Hom.: 2 Cov.: 33 AF XY: 0.000778 AC XY: 565AN XY: 726640
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GnomAD4 genome AF: 0.000901 AC: 134AN: 148792Hom.: 0 Cov.: 33 AF XY: 0.000920 AC XY: 67AN XY: 72800
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 20, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2022 | Observed in a patient with hearing loss in published literature (Sommen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 27068579) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | OTOF: PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 14, 2019 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 21, 2018 | The p.Arg544Cys variant in OTOF has been identified in 1 individual with autosom al recessive sensorineural hearing loss who carried a second OTOF variant of unc ertain significance; it is unclear whether these variants are in trans (Sommen 2 016). The p.Arg544Cys variant has also been identified by our laboratory in 6 in dividuals with hearing loss; however, none of these individuals carried a varian t affecting the other copy of the OTOF gene or was reported to have auditory neu ropathy typically associated with OTOF related hearing loss. This variant has be en reported in ClinVar (Variation ID: 48176). It has been identified in 0.15% (1 93/125430) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org); however, this frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation anal ysis suggest that the p.Arg544Cys variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, the c linical significance of the p.Arg544Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, BS1_Supporting. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2023 | Variant summary: OTOF c.1630C>T (p.Arg544Cys) results in a non-conservative amino acid change located in the Ferlin, third C2 domain (IPR037722) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 249668 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00077 vs 0.0011), allowing no conclusion about variant significance. c.1630C>T has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss without evidence of cosegregation (Kothiyal_2010, Sommen_2016). These reports do not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 9. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variants as likely benign (n=1) or uncertain significance (n=7). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Autosomal recessive nonsyndromic hearing loss 9 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 16, 2022 | - - |
Hearing impairment Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PP3_Supporting - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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