rs921891243
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_194248.3(OTOF):āc.2896A>Gā(p.Met966Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,456 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 Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
OTOF
NM_194248.3 missense
NM_194248.3 missense
Scores
1
5
11
Clinical Significance
Conservation
PhyloP100: 5.03
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 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.26640353).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.2896A>G | p.Met966Val | missense_variant | 24/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.655A>G | p.Met219Val | missense_variant | 7/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.2896A>G | p.Met966Val | missense_variant | 24/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.655A>G | p.Met219Val | missense_variant | 7/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460456Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726520
GnomAD4 exome
AF:
AC:
1
AN:
1460456
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
726520
Gnomad4 AFR exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Alfa
AF:
Hom.:
Bravo
AF:
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 | Jul 13, 2017 | The p.Met966Val variant in OTOF has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational pr ediction tools and conservation analyses do not provide strong support for or ag ainst an impact to the protein. In summary, the clinical significance of the p.M et966Val variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
T
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;.;P;.;B
Vest4
MutPred
0.49
.;.;.;Loss of MoRF binding (P = 0.1284);Loss of MoRF binding (P = 0.1284);.;
MVP
MPC
0.40
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