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Compound heterozygous variants across variant types

As discussed in other sections, the Genomics England bioinformatics pipeline will prioritise small variants, copy number variants and short tandem repeat expansions when they fulfil certain criteria.

If a gene is associated with biallelic modes of inheritance then variants that are in compound heterozygosity across variant types (e.g. a SNV and a CNV) are also considered together during variant prioritisation.

In order to be considered as a compound heterozygous variant across variant types, the variants must impact a PanelApp green gene on the applied panel, with a biallelic mode of inheritance.

In addition:

  • CNVs must fulfil all criteria required to be classified as Tier A
  • STRs must fulfil other criteria to be considered as a Tier 1 or Tier 2 variant, i.e. have an upper confidence interval beyond the expansion thresholds in PanelApp1
  • Small variants must fulfil other criteria to be considered as a Tier 1 or Tier 2 variant, including population frequency, consequence type and/or pathogenicity status1

Note

1In order for STRs and small variants to be considered as Tier1 or Tier2, they must segregate appropriately with the stated mode of inheritance in PanelApp. For biallelic genes, this approach considers variants impacting the gene across the different variant types (Copy Number Variants, Short Tandem Repeat expansions, small insertions, small deletions and single nucleotide variants).

Note

Genes that are not green in the applied gene panel will not include consideration of compound heterozygous variants across variant types. For example, a CNV assigned to Tier Null will not be considered in combination with a small variant assigned to Tier 3.

Tiering of compound heterozygous variants across variant types can be applied for singletons and for probands referred with other family members.

Unlike small variants analysed in trios - which considers variant phase during prioritisation - the phase of CNVs and STRs are not considered. Scientists reviewing groups of variants across variant types are recommended to assess segregation of variants in the family to inform whether the variants are in-cis or in-trans.

Note

de novo small variants are considered during tiering of compound heterozygous variants