rs552304627
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_001292063.2(OTOG):c.385G>A(p.Val129Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,550,382 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 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 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.385G>A | p.Val129Met | missense_variant, splice_region_variant | 5/56 | ENST00000399397.6 | |
OTOG | NM_001277269.2 | c.421G>A | p.Val141Met | missense_variant, splice_region_variant | 4/55 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.385G>A | p.Val129Met | missense_variant, splice_region_variant | 5/56 | 5 | NM_001292063.2 | P2 | |
OTOG | ENST00000399391.7 | c.421G>A | p.Val141Met | missense_variant, splice_region_variant | 4/55 | 5 | A2 | ||
OTOG | ENST00000428619.1 | c.202G>A | p.Val68Met | missense_variant, splice_region_variant | 3/4 | 3 | |||
OTOG | ENST00000498332.5 | n.291G>A | splice_region_variant, non_coding_transcript_exon_variant | 4/16 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000835 AC: 127AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000880 AC: 130AN: 147698Hom.: 1 AF XY: 0.000892 AC XY: 71AN XY: 79616
GnomAD4 exome AF: 0.000914 AC: 1278AN: 1398080Hom.: 3 Cov.: 32 AF XY: 0.000899 AC XY: 620AN XY: 689586
GnomAD4 genome ? AF: 0.000834 AC: 127AN: 152302Hom.: 0 Cov.: 33 AF XY: 0.000859 AC XY: 64AN XY: 74474
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 21, 2023 | The p.Val141Met variant in OTOG has been previously reported in 1 individual with hearing loss, but a variant affecting the remaining copy of OTOG was not identified (LMM data). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 229094) and has been identified in 1.3% (4/316) of Middle Eastern and 0.17% (27/15286) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is located in the last base of the exon, which is part of the 5’ splice region. Splice site computational tools suggest a possible impact to splicing, however, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val141Met variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | OTOG: PP3, BS1:Supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 141 of the OTOG protein (p.Val141Met). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs552304627, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 229094). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Meniere disease Pathogenic:1
Likely pathogenic, flagged submission | case-control | Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO) | Jan 01, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Autosomal recessive nonsyndromic hearing loss 18B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 16, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at