rs111033405
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_194248.3(OTOF):āc.4718T>Cā(p.Ile1573Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.000032 ( 0 hom. )
Consequence
OTOF
NM_194248.3 missense
NM_194248.3 missense
Scores
13
3
1
Clinical Significance
Conservation
PhyloP100: 9.32
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 Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
?
Variant 2-26465753-A-G is Pathogenic according to our data. Variant chr2-26465753-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26465753-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.4718T>C | p.Ile1573Thr | missense_variant | 38/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.2417T>C | p.Ile806Thr | missense_variant | 21/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.4718T>C | p.Ile1573Thr | missense_variant | 38/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.2417T>C | p.Ile806Thr | missense_variant | 21/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251476Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135918
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GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727248
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74358
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 04, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The missense c.4718T>C (p.Ile1573Thr) variant in the OTOF gene has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nonsyndromic Hearing Loss and Deafness, Type 9 (Iwasa, Yoh-Ichiro et al.,2022) . This variant is reported with the allele frequency (0.003%) in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Isoleucine at position 1573 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. The variant is predicted as damaging by SIFT. The amino acid change p.Ile1573Thr in OTOF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. - |
Bilateral sensorineural hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo | - | This variant was detected in homozygosisi in na sporadic case of HL, born from a consanguineous marriage, segregsation confirmed - |
Nonsyndromic genetic hearing loss Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 08, 2021 | Variant summary: OTOF c.4718T>C (p.Ile1573Thr) results in a non-conservative amino acid change located in the sixth C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251476 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss and Deafness, Type 9 (0.0011), allowing no conclusion about variant significance. c.4718T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nonsyndromic Hearing Loss and Deafness, Type 9 (Duman_2011, Yildirim-Baylan_2014, Sloan-Heggen_2015, Iwasa_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1573 of the OTOF protein (p.Ile1573Thr). This variant is present in population databases (rs111033405, gnomAD 0.008%). This missense change has been observed in individual(s) with deafness (PMID: 21117948, 24746455, 34536124). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48240). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OTOF protein function. For these reasons, this variant has been classified as Pathogenic. - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 02, 2008 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
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
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D;D;.
Sift4G
Pathogenic
D;D;.;D;D;.
Polyphen
D;D;.;D;.;D
Vest4
MVP
MPC
0.74
ClinPred
D
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