rs113433719
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_194248.3(OTOF):c.3091A>G(p.Ile1031Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
OTOF
NM_194248.3 missense
NM_194248.3 missense
Scores
4
13
Clinical Significance
Conservation
PhyloP100: 5.11
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 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.25993314).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.3091A>G | p.Ile1031Val | missense_variant | 25/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.850A>G | p.Ile284Val | missense_variant | 8/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.3091A>G | p.Ile1031Val | missense_variant | 25/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.850A>G | p.Ile284Val | missense_variant | 8/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250740Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135826
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460886Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 726752
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152274Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74458
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
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 | Jun 07, 2016 | The p.Ile1031Val variant in OTOF has not been previously reported in individuals with hearing loss. This variant has been identified in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs113433719). Although this variant has been seen in the general po pulation, its frequency is not high enough to rule out a pathogenic role. Comput ational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the p.Ile1031Val vari ant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N;N;.
REVEL
Benign
Sift
Benign
T;T;.;T;T;.
Sift4G
Benign
T;T;.;T;T;.
Polyphen
B;B;.;D;.;P
Vest4
MVP
MPC
0.37
ClinPred
D
GERP RS
Varity_R
gMVP
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