rs150452778
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7
The NM_194248.3(OTOF):c.1530C>T(p.Ile510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000991 in 1,613,320 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I510I) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00089 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0010 ( 0 hom. )
Consequence
OTOF
NM_194248.3 synonymous
NM_194248.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.314
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 2-26482455-G-A is Benign according to our data. Variant chr2-26482455-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48173.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}. Variant chr2-26482455-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.314 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| OTOF | NM_194248.3 | c.1530C>T | p.Ile510= | synonymous_variant | 14/47 | ENST00000272371.7 | |
| OTOF | NM_001287489.2 | c.1530C>T | p.Ile510= | synonymous_variant | 14/46 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| OTOF | ENST00000272371.7 | c.1530C>T | p.Ile510= | synonymous_variant | 14/47 | 1 | NM_194248.3 | A1 | |
| OTOF | ENST00000403946.7 | c.1530C>T | p.Ile510= | synonymous_variant | 14/46 | 5 | P4 |
Frequencies
GnomAD3 genomes 0.000887 AC: 135AN: 152224Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
135
AN:
152224
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000705 AC: 177AN: 250886Hom.: 0 AF XY: 0.000640 AC XY: 87AN XY: 135856
GnomAD3 exomes
AF:
AC:
177
AN:
250886
Hom.:
AF XY:
AC XY:
87
AN XY:
135856
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00100 AC: 1463AN: 1460978Hom.: 0 Cov.: 32 AF XY: 0.000948 AC XY: 689AN XY: 726776
GnomAD4 exome
AF:
AC:
1463
AN:
1460978
Hom.:
Cov.:
32
AF XY:
AC XY:
689
AN XY:
726776
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000886 AC: 135AN: 152342Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61AN XY: 74508
GnomAD4 genome
AF:
AC:
135
AN:
152342
Hom.:
Cov.:
33
AF XY:
AC XY:
61
AN XY:
74508
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 29, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | OTOF: BP4, BP7 - |
| Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 02, 2015 | p.Ile510Ile in exon 14 of OTOF: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (79/65848) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs150452778). - |
OTOF-related disorder Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 28, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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