rs4665855
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The ENST00000402415.8(OTOF):c.-110C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,576,720 control chromosomes in the GnomAD database, including 163,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.47 ( 18095 hom., cov: 32)
Exomes 𝑓: 0.44 ( 145627 hom. )
Consequence
OTOF
ENST00000402415.8 5_prime_UTR
ENST00000402415.8 5_prime_UTR
Scores
10
Clinical Significance
Conservation
PhyloP100: 0.327
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=1.2123064E-6).
BP6
?
Variant 2-26477832-G-A is Benign according to our data. Variant chr2-26477832-G-A is described in ClinVar as [Benign]. Clinvar id is 48191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477832-G-A is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.2215-83C>T | intron_variant | ENST00000272371.7 | |||
OTOF | NM_194323.3 | c.-28+12C>T | intron_variant | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.2215-83C>T | intron_variant | 1 | NM_194248.3 | A1 | |||
OTOF | ENST00000339598.8 | c.-28+12C>T | intron_variant | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? AF: 0.471 AC: 71619AN: 151918Hom.: 18076 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.524 AC: 101448AN: 193584Hom.: 29309 AF XY: 0.516 AC XY: 53561AN XY: 103792
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GnomAD4 exome AF: 0.438 AC: 623898AN: 1424682Hom.: 145627 Cov.: 38 AF XY: 0.440 AC XY: 310290AN XY: 705488
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GnomAD4 genome ? AF: 0.471 AC: 71682AN: 152038Hom.: 18095 Cov.: 32 AF XY: 0.484 AC XY: 35978AN XY: 74320
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1415
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1560
ESP6500AA
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1167
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1821
ExAC
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55243
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | Pro21Leu in exon 1 of OTOF: This variant is not expected to have clinical signif icance because it is has been identified in 5.4% (337/6988) of European American chromosomes and 28.3% (1051/3718) of African American chromosomes from a broad population by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/E VS/; dbSNP rs4665855). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
P;P;P;P;P
Polyphen
B
ClinPred
T
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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