rs67120076
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000531.6(OTC):c.674C>A(p.Pro225Gln) 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. P225R) has been classified as Pathogenic.
Frequency
Consequence
NM_000531.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.674C>A | p.Pro225Gln | missense_variant | 7/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.674C>A | p.Pro225Gln | missense_variant | 9/12 | ||
OTC | XM_017029556.2 | c.674C>A | p.Pro225Gln | missense_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.674C>A | p.Pro225Gln | missense_variant | 7/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000643344.1 | c.*424C>A | 3_prime_UTR_variant, NMD_transcript_variant | 8/11 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1084890Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 351744
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 06, 2020 | 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.Pro225 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27070778, 9427144, 9286441, 1721894). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Tolerated"; 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 proline with glutamine at codon 225 of the OTC protein (p.Pro225Gln). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and glutamine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.