rs80356592
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM5PP3
The NM_194248.3(OTOF):c.2381G>T(p.Arg794Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R794H) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
OTOF
NM_194248.3 missense
NM_194248.3 missense
Scores
9
7
1
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 5.89
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.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr2-26477441-C-T is described in Lovd as [Likely_pathogenic].
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.813
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.2381G>T | p.Arg794Leu | missense_variant | 20/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.140G>T | p.Arg47Leu | missense_variant | 3/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.2381G>T | p.Arg794Leu | missense_variant | 20/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.140G>T | p.Arg47Leu | missense_variant | 3/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1444282Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 716570
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1444282
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
716570
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D;D;.
Sift4G
Pathogenic
D;D;.;D;D;.
Polyphen
D;B;.;B;.;D
Vest4
MutPred
0.57
.;.;.;Loss of methylation at R794 (P = 0.0354);Loss of methylation at R794 (P = 0.0354);.;
MVP
MPC
0.23
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at