rs72556284
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000531.6(OTC):c.533C>T(p.Thr178Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T178T) has been classified as Likely benign.
Frequency
Consequence
NM_000531.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.533C>T | p.Thr178Met | missense_variant | 5/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.533C>T | p.Thr178Met | missense_variant | 7/12 | ||
OTC | XM_017029556.2 | c.533C>T | p.Thr178Met | missense_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.533C>T | p.Thr178Met | missense_variant | 5/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000488812.1 | n.570C>T | non_coding_transcript_exon_variant | 5/6 | 5 | ||||
OTC | ENST00000643344.1 | c.*283C>T | 3_prime_UTR_variant, NMD_transcript_variant | 6/11 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 28
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 13, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 178 of the OTC protein (p.Thr178Met). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OTC protein function. ClinVar contains an entry for this variant (Variation ID: 97237). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 7860066). This variant is not present in population databases (gnomAD no frequency). - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2020 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25958381, 23430554, 16786505, 9452049, 29524203, 11117428, 25994866, 7860066, 25433810, 10946359, 24007980, 18662894, 23829977, 15159648, 17334707, 17565723, 12083811, 23231960, 28324312, 31426867) - |
Pathogenic, no assertion criteria provided | literature only | GenMed Metabolism Lab | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 04, 2021 | This variant appeared to occur de novo in an individual tested at Athena Diagnostics with clinical features associated with this gene. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID: 7860066, 23829977, 25994866, 12083811, 31426867, 17334707, 34014569, 17565723, 29524203, 10946359, 9452049, 11117428, 23430554). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at