rs542442173
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001292063.2(OTOG):c.7975G>A(p.Val2659Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,550,278 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 | UniProt |
---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.7975G>A | p.Val2659Met | missense_variant | 50/56 | ENST00000399397.6 | |
OTOG | NM_001277269.2 | c.8011G>A | p.Val2671Met | missense_variant | 49/55 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.7975G>A | p.Val2659Met | missense_variant | 50/56 | 5 | NM_001292063.2 | P2 | |
OTOG | ENST00000399391.7 | c.8011G>A | p.Val2671Met | missense_variant | 49/55 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000506 AC: 77AN: 152262Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000129 AC: 19AN: 147820Hom.: 0 AF XY: 0.000126 AC XY: 10AN XY: 79516
GnomAD4 exome AF: 0.000122 AC: 171AN: 1397898Hom.: 1 Cov.: 34 AF XY: 0.000112 AC XY: 77AN XY: 689424
GnomAD4 genome ? AF: 0.000499 AC: 76AN: 152380Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29AN XY: 74530
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2671 of the OTOG protein (p.Val2671Met). This variant is present in population databases (rs542442173, gnomAD 0.2%). 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: 227802). 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 methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 04, 2016 | p.Val267Met in exon 49 of OTOG: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, four mammals have a methionine (Met) at this position. It has been identifi ed in 1/5042 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org;dbSNP rs542442173). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at