rs56359117
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001292063.2(OTOG):āc.3229A>Gā(p.Ile1077Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,548,966 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001292063.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.3229A>G | p.Ile1077Val | missense_variant | 27/56 | ENST00000399397.6 | NP_001278992.1 | |
OTOG | NM_001277269.2 | c.3265A>G | p.Ile1089Val | missense_variant | 26/55 | NP_001264198.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.3229A>G | p.Ile1077Val | missense_variant | 27/56 | 5 | NM_001292063.2 | ENSP00000382329 | P2 | |
OTOG | ENST00000399391.7 | c.3265A>G | p.Ile1089Val | missense_variant | 26/55 | 5 | ENSP00000382323 | A2 | ||
OTOG | ENST00000342528.2 | n.594A>G | non_coding_transcript_exon_variant | 4/22 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000565 AC: 86AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000768 AC: 114AN: 148440Hom.: 0 AF XY: 0.000787 AC XY: 63AN XY: 80016
GnomAD4 exome AF: 0.000768 AC: 1073AN: 1396700Hom.: 1 Cov.: 32 AF XY: 0.000749 AC XY: 516AN XY: 688890
GnomAD4 genome AF: 0.000565 AC: 86AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41AN XY: 74456
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 17, 2023 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1089 of the OTOG protein (p.Ile1089Val). This variant is present in population databases (rs56359117, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. 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: 517484). - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 20, 2017 | p.Ile1089Val in exon 26 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 7 mammals have a valine (Val) at this position despite high nearby amino a cid conservation. In addition, computational prediction tools do not suggest a h igh likelihood of impact to the protein. It has also been identified in 0.2% (16 /8400) of Ashkenazi Jewish chromosomes and 0.07% (125/173696) of total chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs56359117). - |
OTOG-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 01, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at