Fig. 4: Breakdown of clinical variants. | Genetics in Medicine

Fig. 4: Breakdown of clinical variants.

From: One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

Fig. 4

(a) Size distribution of pathogenic/likely pathogenic (P/LP) indels and copy-number variants (CNVs), whether technically challenging or not. Sixty-four percent of these variants were 1–5 bp in size (not shown). Single-nucleotide variants (SNVs), FMR1 trinucleotide repeat expansions, and variants in the CFTR poly-T/TG site are not included. (b) Next-generation sequencing (NGS) coverage of P/LP clinical variant locations in the gnomAD database of 125,748 exome sequences (version 2.2.1). The gnomAD genome sequences were not used in this analysis. The average gnomAD exome coverage was 76× at these clinical variant sites (much lower than the 660× average for our clinical testing). The observed rate of a clinical variant location having less than the indicated degree of coverage in the gnomAD exomes was calculated at specific thresholds shown. 5.1% have no coverage (0×), 6.7% less than 10× coverage (including 0×), and 10.1% less than 20×. CNVs were not included in this analysis. (c) Comparison of P/LP clinical variant sites with the Genome in a Bottle (GIAB) benchmark regions using the version 3.3.2 and 4.1 GIAB data sets. Many (9.7%) of these variants were outside of the benchmark regions in all seven GIAB samples (“Not Any” category) and 15.1% of these variants were outside of these regions in at least one of the seven samples (“Not all”). However, the newer version 4.1 GIAB data, available only for one of the GIAB samples at this time, substantially improves this situation. CNVs were not included in this analysis.

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