Figure 2.

Genetic Risk in OrphaNet Conditions

Fold-change of observed genetic risk over expected population prevalence using variant sets from ClinVar for the OrphaNet conditions. Each point represents a condition; each condition may be represented in more than one set. The navy blue line at a fold-change of 10 (i.e., inflation) indicates a theoretical penetrance of 10%. Observations above this line are highly suggestive of misclassified variants. The boxplot shows median (horizontal line in the box), first and third quartile (lower and upper hinges of the box, respectively). The upper whisker extends from the hinge to the largest value no further than 1.5 ^∗ inter-quartile range (IQR) from the hinge. The lower whisker extends from the hinge to the smallest value at most 1.5 ^∗ IQR of the hinge.

(A) Fold-change was calculated using variants per variant set: set 1 consists of variants with 2 or more ClinVar review stars (i.e., two or more submitters with assertion criteria, expert panel, and practice guideline); set 2 consists of variants with 1 star (i.e., one submitter with assertion criteria); set 3 consists of variants with 0 star (i.e., submitter with no assertion criteria submitted in ClinVar); set 4 consists of variants with conflicting interpretations of pathogenicity.

(B) Fold-change was calculated by using variants cumulatively from each set; i.e., set 2 includes set 1 variants, set 3 includes set 1 and 2 variants, set 4 includes all variants.

(C) Fold-change was re-calculated after variants were filtered for disease-specific minor allele frequency thresholds.