rs66656800
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000531.6(OTC):c.386G>A(p.Arg129His) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R129L) has been classified as Pathogenic.
Frequency
Consequence
NM_000531.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.386G>A | p.Arg129His | missense_variant, splice_region_variant | 4/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.386G>A | p.Arg129His | missense_variant, splice_region_variant | 6/12 | ||
OTC | XM_017029556.2 | c.386G>A | p.Arg129His | missense_variant, splice_region_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.386G>A | p.Arg129His | missense_variant, splice_region_variant | 4/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000488812.1 | n.423G>A | splice_region_variant, non_coding_transcript_exon_variant | 4/6 | 5 | ||||
OTC | ENST00000643344.1 | c.*136G>A | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 5/11 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1046247Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 318459
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Oct 19, 2023 | This hemizygous mis-sense variant is identified in a 5 year male with recurrent episodes of lethargy, vomiting, fever, and seizures with encephalopathy and hyperamonemia (256 umol/L). Elder brother of the proband had died at 6 month of age due to encephalopathy. This nucleotide change is absent from the gnomAD database [PM2]. Insilico prediction predicts a deleterious nature of this variant, REVEL score: 0.91 [PP3]. A clinvar entry [Variation id: 11010] of this variant is already present with a "Pathogenic" interpretation [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic". - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 30, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Jul 04, 2019 | This variant has been previously reported as a hemizygous change in patients with ornithine transcarbamylase deficiency (PMID: 7860064, 8081398, 29581464, 30285816). Functional studies revealed that patients carrying this variant in the hemizygous state had reductions of OTC activity to less that 5% of normal levels (PMID: 7860064, 8081398). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.386G>A (p.Arg129His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.386G>A (p.Arg129His) variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 07, 2023 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 11010). This missense change has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 7860064, 8081398, 8807340, 25853564, 29581464, 30285816; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 129 of the OTC protein (p.Arg129His). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | GenMed Metabolism Lab | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at