2-26464029-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_194248.3(OTOF):c.5038C>T(p.Arg1680Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000634 in 1,613,580 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1680H) has been classified as Likely benign.
Frequency
Consequence
NM_194248.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.5038C>T | p.Arg1680Cys | missense_variant | 40/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.2737C>T | p.Arg913Cys | missense_variant | 23/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.5038C>T | p.Arg1680Cys | missense_variant | 40/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.2737C>T | p.Arg913Cys | missense_variant | 23/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes AF: 0.000407 AC: 62AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000411 AC: 103AN: 250712Hom.: 0 AF XY: 0.000354 AC XY: 48AN XY: 135682
GnomAD4 exome AF: 0.000658 AC: 961AN: 1461398Hom.: 0 Cov.: 32 AF XY: 0.000607 AC XY: 441AN XY: 727008
GnomAD4 genome AF: 0.000407 AC: 62AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 26AN XY: 74332
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 17, 2023 | Variant summary: OTOF c.5038C>T (p.Arg1680Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 250712 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00041 vs 0.0011), allowing no conclusion about variant significance. c.5038C>T has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss, however without strong evidence for causality (e.g., Sloan-Heggen_2016). Additionally, one ClinVar submitter reports identifying the variant in at least two heterozygous individuals with hearing loss, however, no second OTOF variant was identified (Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine). These reports do not provide 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. Four ClinVar submitters (evaluation after 2014) have cited the variant, with three submitters classifying the variant as uncertain significance and one submitter classifying the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2016 | The p.Arg1680Cys variant in OTOF has now been identified by our laboratory in th e heterozygous state in 2 individuals with hearing loss, but a second variant af fecting the remaining copy of the gene has not been found in of either individua l. This variant has also been identified in 0.1% (60/65886) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs147070644). Although this variant has been seen in the general populatio n, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1680Cys variant is uncertain. - |
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 | Nov 09, 2021 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at