Figure 2. Comparison of applicable strength for the PS4 criterion between the 2015 ACMG/AMP guidelines and PS4-LRCalc for selected case-control scenarios. Counts of carriers (V⁺) and non-carriers (V⁻) of a variant between cases and controls are illustrated for exemplar scenarios indicative of (A–C) pathogenicity and (D–F) benignity shown in tables2 3. In the PS4-LRCalc approach, the distribution of variant carrier observations between cases and controls is modelled using a binomial likelihood curve, in which the likelihood of association (OR≥5, red) is divided by the likelihood of non-association (OR≤1, blue) to generate a likelihood ratio (LR) towards pathogenicity, that can then be converted to Tavtigian exponent points (EPs) towards pathogenicity or benignity and a corresponding applicable evidence strength under the 2015 ACMG/AMP framework. Notably, our approach allows assignation of EPs for scenarios that may not fulfil the existing ACMG/AMP PS4 guidance, including in support of benignity. ACMG/AMP, American College of Medical Genetics/Association of Molecular Pathology; PS4-LRCalc, PS4-likelihood ratio calculator.