chr2-26457798-A-G
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_194248.3(OTOF):c.*440T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 528,978 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0081 ( 15 hom., cov: 33)
Exomes 𝑓: 0.0020 ( 6 hom. )
Consequence
OTOF
NM_194248.3 3_prime_UTR
NM_194248.3 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.836
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 -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00814 (1238/152020) while in subpopulation AFR AF= 0.0259 (1072/41466). AF 95% confidence interval is 0.0246. There are 15 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 15 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.*440T>C | 3_prime_UTR_variant | 47/47 | ENST00000272371.7 | ||
OTOF | NM_194323.3 | c.*242T>C | 3_prime_UTR_variant | 29/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.*440T>C | 3_prime_UTR_variant | 47/47 | 1 | NM_194248.3 | A1 | ||
OTOF | ENST00000339598.8 | c.*242T>C | 3_prime_UTR_variant | 29/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes AF: 0.00814 AC: 1236AN: 151902Hom.: 15 Cov.: 33
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GnomAD4 exome AF: 0.00199 AC: 751AN: 376958Hom.: 6 Cov.: 3 AF XY: 0.00182 AC XY: 357AN XY: 196622
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GnomAD4 genome AF: 0.00814 AC: 1238AN: 152020Hom.: 15 Cov.: 33 AF XY: 0.00770 AC XY: 572AN XY: 74324
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1
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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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