rs191568463
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_194248.3(OTOF):c.2498A>T(p.Gln833Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000561 in 1,610,944 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00059 ( 1 hom. )
Consequence
OTOF
NM_194248.3 missense
NM_194248.3 missense
Scores
1
7
9
Clinical Significance
Conservation
PhyloP100: 2.65
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 Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.041678667).
BP6
?
Variant 2-26477197-T-A is Benign according to our data. Variant chr2-26477197-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178511.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.2498A>T | p.Gln833Leu | missense_variant | 21/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.257A>T | p.Gln86Leu | missense_variant | 4/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.2498A>T | p.Gln833Leu | missense_variant | 21/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.257A>T | p.Gln86Leu | missense_variant | 4/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? AF: 0.000269 AC: 41AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000552 AC: 135AN: 244384Hom.: 1 AF XY: 0.000631 AC XY: 84AN XY: 133184
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GnomAD4 exome AF: 0.000591 AC: 862AN: 1458644Hom.: 1 Cov.: 33 AF XY: 0.000684 AC XY: 496AN XY: 725470
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GnomAD4 genome ? AF: 0.000269 AC: 41AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74474
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 9 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 28, 2021 | Has not been previously published as pathogenic or benign to our knowledge - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 02, 2017 | p.Gln833Leu in exon 21 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (36/14280) of South Asian Chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs191568463). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D;D;.
REVEL
Uncertain
Sift
Benign
T;T;.;T;T;.
Sift4G
Benign
T;T;.;T;T;.
Polyphen
B;B;.;B;.;P
Vest4
MVP
MPC
0.16
ClinPred
T
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