rs72558412
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000531.6(OTC):c.617T>A(p.Met206Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M206I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000531.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.617T>A | p.Met206Lys | missense_variant | Exon 6 of 10 | ENST00000039007.5 | NP_000522.3 | |
OTC | NM_001407092.1 | c.617T>A | p.Met206Lys | missense_variant | Exon 8 of 12 | NP_001394021.1 | ||
OTC | XM_017029556.2 | c.617T>A | p.Met206Lys | missense_variant | Exon 6 of 9 | XP_016885045.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:1
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met206 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 11793483, 10405441), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with OTC deficiency (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 206 of the OTC protein (p.Met206Lys). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and lysine. -
not provided Pathogenic:1
Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at