PVS1
ASXL1 loss of function is an established disease mechanism, but this variant is a missense substitution, not a nonsense, frameshift, or canonical +/-1 or 2 splice variant, and the generic PVS1 framework does not support applying PVS1 to this change.
PS1
No evidence was identified that the same amino acid change has already been established as pathogenic by a different nucleotide change.
PS2
No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.
PS3
No well-established functional study was identified for this variant, so functional evidence supporting a damaging effect is not available.
PS4
This variant has only limited observation data, with one ClinVar submission and no case-control or enrichment evidence, so increased prevalence in affected individuals has not been shown.
PM1
Available evidence does not show that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation.
PM3
No evidence was identified that this variant was observed in trans with a pathogenic variant in an established recessive disease context.
PM5
No evidence was identified that a different missense change at codon 1268 has already been established as pathogenic.
PM6
No presumed de novo occurrence without confirmed parentage was identified for this variant.
PP1
No segregation data were identified for this variant.
PP2
Available evidence does not establish that ASXL1 missense variation is a common disease mechanism with a low rate of benign missense variation, so PP2 was not applied.
PP3
Available computational evidence does not support a damaging effect.
PP4
No individual-level phenotype data were identified to show a highly specific clinical presentation for a single genetic etiology.
PP5
No reputable source classified this variant as pathogenic, and the available ClinVar entry is uncertain significance rather than a pathogenic assertion supporting PP5.
