X-38401391-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000531.6(OTC):c.503A>G(p.His168Arg) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H168P) has been classified as Pathogenic.
Frequency
Consequence
NM_000531.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.503A>G | p.His168Arg | missense_variant | 5/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.503A>G | p.His168Arg | missense_variant | 7/12 | ||
OTC | XM_017029556.2 | c.503A>G | p.His168Arg | missense_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.503A>G | p.His168Arg | missense_variant | 5/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000488812.1 | n.540A>G | non_coding_transcript_exon_variant | 5/6 | 5 | ||||
OTC | ENST00000643344.1 | c.*253A>G | 3_prime_UTR_variant, NMD_transcript_variant | 6/11 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD4 exome Cov.: 28
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 30, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His168 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 16786505, 9266388), which suggests that this may be a clinically significant amino acid residue. 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. This variant has been observed in individual(s) with OTC deficiency (PMID: 9266387, Invitae). This variant is also known as p.H163R. ClinVar contains an entry for this variant (Variation ID: 97225). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 168 of the OTC protein (p.His168Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. - |
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