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There is discussion of expanding newborn screening (NBS) through the use of genomic sequence data; yet, challenges remain in the interpretation of DNA variants. Population-level DNA variant databases are available, and it is possible to estimate the number of newborns who would be flagged as having a risk for a genetic disease (including rare variants of unknown significance, VUS) via next-generation sequencing (NGS) positive. Estimates of the number of newborns screened as NGS positive for monogenic recessive diseases were obtained by analysis of the Genome Aggregation Database (gnomAD). For a collection of diseases for which there is interest in NBS, we provided 2 estimates for the expected number of newborns screened as NGS positive. For a set of lysosomal storage diseases, we estimated that 100 to approximately 600 NGS screen positives would be found per disease per year in a large NBS laboratory (California), and this figure may be expected to rise to a limit of about 1000 if we account for the fact that gnomAD does not contain all worldwide variants. The number of positives would drop 2.5- to 10-fold if the 10 VUS with highest allele frequency were biochemically annotated as benign. It is proposed that a second-tier biochemical assay using the same dried blood spot could be carried out as a filter and as part of NBS to reduce the number of high-risk NGS positive newborns to a manageable number.