rs754883697
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001292063.2(OTOG):c.8541+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000871 in 1,550,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.8541+5G>A | splice_region_variant, intron_variant | Intron 55 of 55 | ENST00000399397.6 | NP_001278992.1 | ||
OTOG | NM_001277269.2 | c.8577+5G>A | splice_region_variant, intron_variant | Intron 54 of 54 | NP_001264198.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.8541+5G>A | splice_region_variant, intron_variant | Intron 55 of 55 | 5 | NM_001292063.2 | ENSP00000382329.2 | |||
OTOG | ENST00000399391.7 | c.8577+5G>A | splice_region_variant, intron_variant | Intron 54 of 54 | 5 | ENSP00000382323.2 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152268Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000147 AC: 22AN: 149252Hom.: 0 AF XY: 0.000174 AC XY: 14AN XY: 80378
GnomAD4 exome AF: 0.0000872 AC: 122AN: 1398322Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 76AN XY: 689692
GnomAD4 genome AF: 0.0000853 AC: 13AN: 152386Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74526
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2025 | Has not been previously published as pathogenic or benign to our knowledge; Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 21, 2024 | This sequence change falls in intron 54 of the OTOG gene. It does not directly change the encoded amino acid sequence of the OTOG protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs754883697, gnomAD 0.08%). This variant has been observed in individual(s) with clinical features of OTOG-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 505108). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 21, 2016 | The c.8577+5G>A variant in OTOG has not been previously reported in individuals with hearing loss. This variant has been identified in 0.4% (1/286) of Latino ch romosomes and in 0.1% (7/7640) of South Asian chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs754883697). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the c.8577+5G>A variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at