11-112226468-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000317.3(PTS):c.25C>T(p.Arg9Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,428,804 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 Uncertain significance (★).
Frequency
Consequence
NM_000317.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000210 AC: 3AN: 1428804Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1AN XY: 707384
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: PTS c.25C>T (p.Arg9Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 192406 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.25C>T, has been reported in the literature in a compound heterozygous individual affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (Leuzzi_2009, Manti_2020), this individual carried a reportedly pathogenic missense variant in trans, and was reported to have PTS enzyme deficiency, measured in patient derived cells (Leuzzi_2009). At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that this variant doesn't affect homodimerization of the PTS enzyme (Das_2014), however, these results do not allow any conclusions about the variant effect on enzyme activity. Another missense variant affecting the same residue (c.26G>A (p. Arg9His)) was reported in affected individuals (HGMD), supporting a potential functional role for this residue in protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at