Fig. 3: mLOF score and phenotype semantic similarity prioritise dominant-negative phenotypes in AD/ARmixed genes. | Nature Communications

Fig. 3: mLOF score and phenotype semantic similarity prioritise dominant-negative phenotypes in AD/ARmixed genes.

From: Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes

Fig. 3

a ΔΔGrank distributions for disease phenotypes in exclusively recessive genes (AR) and recessive phenotypes in AD/ARmixed genes ([AR]- AD/ARmixed). Boxes represent data within the 25th and 75th percentiles, the middle line is the median, the notches contain the 95% confidence interval of the median, and the whiskers extend to 1.5× the interquartile range. The P-value represents a two-sided Wilcoxon rank-sum test. b Comparison of AD-AR phenotype semantic similarity within [AR]- AD/ARmixed genes, split into whether the variants of the AD phenotype are predicted to have a non-LOF effect. The P-value represents a two-sided Wilcoxon rank-sum test. c CLCN7, which encodes the H(+)/Cl(-) exchange transporter 7, is an example of an AD/ARmixed gene with a reported DN mechanism of pathogenesis. Its structure represents the AlphaFold-predicted model (P51798 [https://alphafold.ebi.ac.uk/files/AF-P51798-F1-model_v1.pdb]). Missense variant positions are shown for the dominant (OPTA2) and recessive (OPTB4) forms of osteopetrosis, with their corresponding mLOF scores displayed below. Regions below a pLDDT of 70 are shown in purple. Source data are provided as a Source Data file.

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