rs397515581
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_194248.3(OTOF):βc.1236delβ(p.Glu413AsnfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P412P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_194248.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.1236del | p.Glu413AsnfsTer9 | frameshift_variant | 13/47 | ENST00000272371.7 | |
OTOF | NM_001287489.2 | c.1236del | p.Glu413AsnfsTer9 | frameshift_variant | 13/46 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.1236del | p.Glu413AsnfsTer9 | frameshift_variant | 13/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000403946.7 | c.1236del | p.Glu413AsnfsTer9 | frameshift_variant | 13/46 | 5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460588Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726572
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 65775). This premature translational stop signal has been observed in individual(s) with auditory neuropathy spectrum disorder and/or bilateral nonsyndromic deafness (PMID: 18381613, 25788563, 30065612). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu413Asnfs*9) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at