chr2-26475949-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_194248.3(OTOF):c.2956C>T(p.Arg986Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,611,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
OTOF
NM_194248.3 missense
NM_194248.3 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 1.31
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.83
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.2956C>T | p.Arg986Cys | missense_variant | 24/47 | ENST00000272371.7 | NP_919224.1 | |
OTOF | NM_194323.3 | c.715C>T | p.Arg239Cys | missense_variant | 7/29 | ENST00000339598.8 | NP_919304.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.2956C>T | p.Arg986Cys | missense_variant | 24/47 | 1 | NM_194248.3 | ENSP00000272371.2 | ||
OTOF | ENST00000339598.8 | c.715C>T | p.Arg239Cys | missense_variant | 7/29 | 1 | NM_194323.3 | ENSP00000344521.3 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152098Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000811 AC: 20AN: 246528Hom.: 0 AF XY: 0.0000822 AC XY: 11AN XY: 133830
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GnomAD4 exome AF: 0.000112 AC: 163AN: 1459330Hom.: 0 Cov.: 33 AF XY: 0.000105 AC XY: 76AN XY: 725824
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74424
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 15, 2016 | The p.Arg986Cys variant in OTOF has not been previously reported in individuals with hearing loss, but has been identified in 9/50616 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20 1198797). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg986Cys variant is uncertain. - |
Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;.;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;.;.;M;M;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;D;D;.
REVEL
Uncertain
Sift
Pathogenic
D;D;.;D;D;.
Sift4G
Pathogenic
D;D;.;D;D;.
Polyphen
D;D;.;D;.;D
Vest4
MVP
MPC
0.77
ClinPred
D
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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