chr2-26473999-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_194248.3(OTOF):c.3400C>T(p.Arg1134*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,612,920 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_194248.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.3400C>T | p.Arg1134* | stop_gained | Exon 27 of 47 | 1 | NM_194248.3 | ENSP00000272371.2 | ||
OTOF | ENST00000339598.8 | c.1159C>T | p.Arg387* | stop_gained | Exon 10 of 29 | 1 | NM_194323.3 | ENSP00000344521.3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152072Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250522Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135736
GnomAD4 exome AF: 0.000107 AC: 157AN: 1460730Hom.: 0 Cov.: 32 AF XY: 0.0000963 AC XY: 70AN XY: 726702
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74402
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 34599368, 26188103, 34652575, 18381613, 37677959, 19461658) -
This sequence change creates a premature translational stop signal (p.Arg1134*) 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). This variant is present in population databases (rs199848801, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with nonsyndromic deafness (PMID: 18381613, 26188103). ClinVar contains an entry for this variant (Variation ID: 65798). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:1Other:1
in compound heterozygosis with the c.3049C>A variant in two siblings with bilateral non-syndromic prelingual auditory neuropathy (familial) -
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Bilateral sensorineural hearing impairment Pathogenic:1
The c.3400C>T variant was found in homozygosis in a subjetvt with non-syndromic auditory neuropathy and leads to a premature stop codon, a common mutational mechanism in OTOF -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at