Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting Caroline F. Wright, Ben West,

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Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting Caroline F. Wright, Ben West, Marcus Tuke, Samuel E. Jones, Kashyap Patel, Thomas W. Laver, Robin N. Beaumont, Jessica Tyrrell, Andrew R. Wood, Timothy M. Frayling, Andrew T. Hattersley, Michael N. Weedon The American Journal of Human Genetics Volume 104, Issue 2, Pages 275-286 (February 2019) DOI: 10.1016/j.ajhg.2018.12.015 Copyright © 2019 The Authors Terms and Conditions

Figure 1 Correlation between Minor Allele Frequency and Analytical Validity Quality Score (A and B) Density plot (A) and boxplot (B) of manual quality scores (from 1–5, see Figure S1) of genotype data in UKB versus minor allele frequency (MAF) for 4,585 putatively clinically important variants, where MAF < 1%, Hardy–Weinberg equilibrium (HWE) > 0.05, and missingness < 0.01. (C) Histogram of the number of variants at each quality score versus presence or absence of the variant in gnomAD (exome data) or the 1000 Genomes Project. Red = score 1; gold = score 2; green = score 3; blue = score 4; purple = score 5. (D) Estimation of the false-positive rate (FPR) versus MAF for variants assayed with the UKB genotyping arrays, calculated by the grouping of quality scores into low (score = 1 or 2) and high (score = 4 or 5) and use of the rocreg command in Stata for fitting a ROC curve. The American Journal of Human Genetics 2019 104, 275-286DOI: (10.1016/j.ajhg.2018.12.015) Copyright © 2019 The Authors Terms and Conditions

Figure 2 Comparison of Penetrance Estimate for HNF4A p.Arg114Trp in UK Biobank versus Previously Published Estimates from MODY Cohort Studies A Kaplan-Meier plot of the proportion of individuals who are diabetes free at various ages for 379,768 individuals from UK Biobank (red line), 122 UK Biobank individuals who are heterozygous for HNF4A p.Arg114Trp (green line), 26 MODY referral probands (blue line), and 24 family members of the probands (yellow line) from Laver et al.54 The American Journal of Human Genetics 2019 104, 275-286DOI: (10.1016/j.ajhg.2018.12.015) Copyright © 2019 The Authors Terms and Conditions