Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

Table 3 Clinically significant sequence variants uncovered by the deletions. Subjects #1 and #2 were identified in a COX10-phenotype-driven cohort analysis. Subjects #1, #3, and #4 were identified in the molecular-deletion-driven clinical exome data reanalysis

ID	Deletion/ allele frequency	Gene (RefSeq transcript)	Genic variant	Genomic coordinate (GRCh38)	MAF in gnomAD v3.1	Classification	Category
1	17p12 HNPP/ 3.148 × 10⁻⁴	COX10 (NM_001303.3)	c.1277_1282dup (p.M426_L427dup)	chr17:14207158_ 14207163dup	0	VUS	NDAC
2	17p12 HNPP/ 3.148 × 10⁻⁴	COX10 (NM_001303.3)	c.858G>T (p.W286C)	chr17:14192151G>T	6.567 × 10⁻⁶	VUS	NDAC
3	10q11.21q11.23 deletion/ 1.353 × 10⁻⁴	ERCC6 (NM_000124.3)	c.1490T>C (p.F497S)	chr10:49505920A>G	0	VUS	NDAC
4	15q13.3 BP4-BP5 deletion/ 9.97 × 10⁻⁵	OTUD7A (NM_130901.2)	c.2023_2066del (p.D675Hfs*188)	chr15:31484009_ 31484052del	6.58 × 10^{−5 a}	VUS	NDGMC
5	16p11.2 proximal / 5.076 × 10⁻⁴	PRRT2 (NM_145239.2)	c.649dup (p.R217fs*8)	chr16: 29813703dup	1.472 × 10^{−4 b}	Pathogenic	NDGMC

^aThis variant is marked with “low complexity region” label in gnomAD, suggesting ambiguous variant call quality. It has a variant count of 2 in gnomAD v3.1. However, manual review of the alignment data from gnomAD suggests only 1 is of higher quality. The allele frequency is adjusted in half accordingly
^bThis variant is marked with “low complexity region” label in gnomAD, suggesting ambiguous variant call quality. It is located in a homopolymer region that is susceptible to false positive variant calling. The variant allele frequency quoted here may be overestimated
Abbreviations: MAF, minor allele frequency; VUS, variant of unknown clinical significance; NDAC, new disease allele characterization; NDGMC, new disease gene/mechanism characterization

ISSN: 1756-994X