11-112226489-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000317.3(PTS):c.46C>T(p.Arg16Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,586,340 control chromosomes in the GnomAD database, with no homozygous occurrence. 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_000317.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000198 AC: 4AN: 202108Hom.: 0 AF XY: 0.0000183 AC XY: 2AN XY: 109100
GnomAD4 exome AF: 0.0000314 AC: 45AN: 1434196Hom.: 0 Cov.: 31 AF XY: 0.0000281 AC XY: 20AN XY: 710510
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:1Uncertain:1
The PTS c.46C>T (p.Arg16Cys) missense variant has been reported in one study in which it is found in a compound heterozygous state with a frameshift variant in one individual with 6-pyruvoyltetrahydropterin synthase deficiency (Thöny et al. 1994). Control data are unavailable for this variant, which is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele only and is presumed to be rare. Characterization of patient fibroblasts revealed PTS activity equivalent to one percent of wild type and heterologous expression of the p.Arg16Cys enzyme in E. coli showed similar expression levels but only seven percent enzyme activity of wild type (Thöny et al. 1994). Expression of variant p.Arg16Cys and the mouse equivalent (mPTPSp.Arg15Cys) in COS-1 cells revealed significantly reduced PTS activity and in vivo radioactive labelling experiments showed that wild PTS was phosphorylated but the p.Arg16Cys was not (Oppliger et al. 1995; Korner et al. 2016). Mice that were homozygous or compound heterozygous for variant p.Arg16Cys had reduced PTPS activity (Korner et al. 2016). Based on the evidence, the p.Arg16Cys variant is classified as a variant of uncertain significance but suspicious for pathogenicity for 6-pyruvoyltetrahydropterin synthase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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Hyperphenylalaninemia, bh4-deficient, a, due to partial pts deficiency Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at