Even for extremely rare variants with sample minor allele count (MAC) <10 (including cohort singleton variants in the target JHS cohort), average information content rescued (again measured by true R2) was >86%. For example, out of the 8.67 million singleton variants discovered in JHS by TOPMed WGS, 72% (6.24 million) can be well-imputed using Affymetrix 6.0 genotypes and using TOPMed freeze 5b (without JHS individuals) as reference, with an average true R2 of 0.92 (Table 2). Singletons within JHS are defined as variants with MAC = 1 among the JHS samples but which are present in multiple copies in the reference panel. Specifically, the average reference MAC is 29.3 before post-imputation quality control (QC) and 31.0 after QC, with all variants having a MAC>5 in the overall reference panel. Imputation quality is similarly high when examining extremely rare MAC variants in the reference panel, and even higher, as expected, with higher MAC variants within the JHS sample (S4 and S5 Tables). Similar observations hold true for HCHS/SOL, with slightly lower imputation quality (S6 and S7 Tables). Compared to JHS African
