Fig. 2

Four-way classification of PTEN variants. A Scatterplot of PTEN variants scored in both assays, with abundance scores shown on the x-axis, and phosphatase scores shown on the y-axis. WT-like variants are shown in green, loss of activity variants are shown in orange, loss of abundance variants are shown in cyan, and variants that have both losses in activity and abundance are shown in purple. The total counts of the classified or unclassified (gray) variants in each sector of the plot are shown. B Scatterplot of activity scores and individually assessed EGFP fluorescence for 20 variants. Variants at known catalysis affecting residues 45, 124, and 129, as well as PIP₂ binding residues 1 through 13, were removed from the analysis. C Scatterplot of ClinVar pathogenic or CC cohort PHTS or autism spectrum disorder (ASD) variants with low abundance, plotted by abundance and activity scores. Variants that did not score as low for activity are labeled. D Positions with variants of extreme effects shown on the PTEN crystal structure (pdb: 1d5r). E (Top) Bar chart showing the distribution of the abundance and activity PTEN variant subsets across the various clinical groupings. (Bottom) The fraction of each variant class for each category was divided by the fraction of the corresponding variant class in the All SNV category to calculate the fold enrichment or depletion. The PHTS category includes ClinVar pathogenic or likely pathogenic PTEN variants for PHTS, and variants from patients identified with PHTS in the CC cohort. The ASD category includes variants listed in the SFARI Gene database, and variants from patients identified with ASD or developmental disorders in the CC cohort. Variants associated with both were put in their own category of PHTS & ASD. VUS are variants of uncertain significance in ClinVar. PTEN variants observed in unaffected populations captured by the GnomAD and TOPMed databases are also shown