X-38421078-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000531.6(OTC):āc.1061T>Gā(p.Phe354Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000423 in 1,181,148 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000531.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.1061T>G | p.Phe354Cys | missense_variant | Exon 10 of 10 | 1 | NM_000531.6 | ENSP00000039007.4 | ||
ENSG00000250349 | ENST00000465127.1 | c.172-245043T>G | intron_variant | Intron 3 of 8 | 5 | ENSP00000417050.1 | ||||
OTC | ENST00000643344.1 | n.*811T>G | downstream_gene_variant | ENSP00000496606.1 |
Frequencies
GnomAD3 genomes AF: 0.00000897 AC: 1AN: 111431Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33633
GnomAD3 exomes AF: 0.00000547 AC: 1AN: 182812Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67428
GnomAD4 exome AF: 0.00000374 AC: 4AN: 1069717Hom.: 0 Cov.: 25 AF XY: 0.00000296 AC XY: 1AN XY: 337543
GnomAD4 genome AF: 0.00000897 AC: 1AN: 111431Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33633
ClinVar
Submissions by phenotype
Ornithine carbamoyltransferase deficiency Pathogenic:5Uncertain:1
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The OTC c.1061T>G (p.F354C) variant was previously reported in mild ornithine transcarbamylase deficiency (PMID: 8857803; 16786505). -
Variant summary: OTC c.1061T>G (p.Phe354Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182812 control chromosomes. c.1061T>G has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in less than 2% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 354 of the OTC protein (p.Phe354Cys). This variant is present in population databases (rs72558495, gnomAD 0.001%). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 9266388, 10869432). ClinVar contains an entry for this variant (Variation ID: 97104). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt OTC protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
This missense variant replaces phenylalanine with cysteine at the last amino acid codon 354 of the OTC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a 13-year old boy diagnosed with late-onset ornithine transcarbamylase deficiency based on hyperammonemia and 1.8% residual OTC enzyme activity detected in his liver tissue frozen at autopsy (PMID: 8857803). This variant has been observed in a male with first presentation of hyperammonemia at age 14, as well as in his 55-year old, asymptomatic grandfather (PMID: 10946359). OTC enzyme activity was not determined in the proband. This variant has also been observed in a newborn girl diagnosed with phenylketonuria and unaffected with symptoms of ornithine transcarbamylase deficiency (PMID: 32853555). Her grandfather and younger male sibling were unaffected carriers of this variant. This variant has been identified in 1/182812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Pathogenic:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9266388, 8857803, 28324312, 16786505, 32853555, 37146589, 11793468, 10869432, 10946359) -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at