rs548496846
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_001292063.2(OTOG):c.7693+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,540,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001292063.2 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.7693+1G>A | splice_donor_variant, intron_variant | ENST00000399397.6 | NP_001278992.1 | |||
OTOG | NM_001277269.2 | c.7729+1G>A | splice_donor_variant, intron_variant | NP_001264198.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.7693+1G>A | splice_donor_variant, intron_variant | 5 | NM_001292063.2 | ENSP00000382329.2 | ||||
OTOG | ENST00000399391.7 | c.7729+1G>A | splice_donor_variant, intron_variant | 5 | ENSP00000382323.2 | |||||
OTOG | ENST00000342528.2 | n.4606-422G>A | intron_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.000875 AC: 133AN: 152072Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000697 AC: 95AN: 136276Hom.: 0 AF XY: 0.000634 AC XY: 47AN XY: 74082
GnomAD4 exome AF: 0.00151 AC: 2090AN: 1387974Hom.: 0 Cov.: 33 AF XY: 0.00142 AC XY: 969AN XY: 684660
GnomAD4 genome AF: 0.000874 AC: 133AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50AN XY: 74386
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | OTOG: PVS1:Moderate, BS1:Supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2024 | Observed without another OTOG variant in a patient with hearing loss in published literature (PMID: 29196752); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29196752) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 25, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | This sequence change affects a donor splice site in intron 45 of the OTOG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). This variant is present in population databases (rs548496846, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with deafness (PMID: 29196752). ClinVar contains an entry for this variant (Variation ID: 488980). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Autosomal recessive nonsyndromic hearing loss 18B Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 25, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 06, 2018 | Variant classified as Uncertain Significance - Favor Pathogenic. The c.7729+1G>A variant in OTOG has been reported in the heterozygous state in one individual w ith hearing loss (Baux 2017) and has been identified by our laboratory in the he terozygous state in 2 individuals with hearing loss, both of whom had pathogenic variants in other genes sufficient to explain their hearing loss. This variant has also been identified in 0.2% (101/60880) of European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs5484 96846). Although this variant has been seen in the general population, its frequ ency is not high enough to rule out a pathogenic role. This variant occurs in th e invariant region (+/- 1,2) of the splice consensus sequence of exon 45; howeve r, exon 45 is in-frame and it is unclear if altered splicing will lead to an in- frame deletion of exon 45 or an absent protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.7729+1G>A va riant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at