rs72853726
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_194248.3(OTOF):c.4629-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,614,234 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.012 ( 26 hom., cov: 33)
Exomes 𝑓: 0.0024 ( 42 hom. )
Consequence
OTOF
NM_194248.3 splice_polypyrimidine_tract, intron
NM_194248.3 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00001618
2
Clinical Significance
Conservation
PhyloP100: -1.33
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 (BayesDel_noAF=-0.84).
BP6
?
Variant 2-26465851-G-A is Benign according to our data. Variant chr2-26465851-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1790/152360) while in subpopulation AFR AF= 0.0373 (1552/41578). AF 95% confidence interval is 0.0358. There are 26 homozygotes in gnomad4. There are 855 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 26 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.4629-9C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000272371.7 | |||
OTOF | NM_194323.3 | c.2328-9C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.4629-9C>T | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_194248.3 | A1 | |||
OTOF | ENST00000339598.8 | c.2328-9C>T | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0117 AC: 1776AN: 152242Hom.: 25 Cov.: 33
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GnomAD3 exomes AF: 0.00456 AC: 1146AN: 251350Hom.: 19 AF XY: 0.00394 AC XY: 536AN XY: 135878
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GnomAD4 exome AF: 0.00243 AC: 3551AN: 1461874Hom.: 42 Cov.: 32 AF XY: 0.00237 AC XY: 1721AN XY: 727232
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GnomAD4 genome ? AF: 0.0117 AC: 1790AN: 152360Hom.: 26 Cov.: 33 AF XY: 0.0115 AC XY: 855AN XY: 74494
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 16, 2011 | 4629-9C>T in exon 38 of OTOF: This variant is not expected to have clinical sign ificance because it has been identified in 3.9% (147/3738) of chromosomes from a broad African American population and 0.15% (11/7020) of chromosomes from a bro ad European American population (dbSNP rs72853726). - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2018 | 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. - |
Autosomal recessive nonsyndromic hearing loss 9 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at