Scripps Genome ADVISER | Annotation and Distributed Variant Interpretation Server
Scripps Genome ADVISER | Annotation and Distributed Variant Interpretation Server

ADVISER Scoring Table


In brief, the ADVISER scoring guidelines (Richards et al 2008) with categories 1-6 are modified to include categories 1*, 2* and 4* to provide more granularity to variant stratification. Variants of category 1-2* are of most clinical relevance and category 6 contains more common risk factors for disease. ADVISER category 1 variants are rare ( < 1% allele frequency) variants reported in the literature with good evidence for causality in disease. Category 1* includes uncommon variants (1-5% or 1-10% allele frequency depending upon the level of evidence) associated with disease, but are perhaps incompletely penetrant or of lower confidence. Category 2 variants are novel rare variants in known disease genes predicted to impact gene function by either removing a splice site donor or acceptor, producing an amino acid substitution predicted to functionally impact the protein, or truncating the protein in a damaging manner. Category 2* includes truncating variants not predicted to damage protein function. Variants less confidently predicted to be associated with disease, either through neutral coding changes or impact upon regulatory function are placed in categories 3, 4, and 4* with predicted neutral variants and known phenotype associated variants assigned to categories 5 and 6 respectively.

Category 1: sequence variation is previously reported and is a recognized cause of the disorder
  • Sequence variant is reported in the literature as causal to disease
  • Variant is rare

Category 1*: sequence variation is previously reported and is a recognized cause of the disorder (lower confidence or incompletely penetrant)
  • Sequence variant is reported in the literature as causal to disease
  • Variant is uncommon

Category 2: sequence variation is previously unreported and is of the type that is expected to cause the disorder
  • Variant is rare
  • Variant is predicted to damage protein function with high confidence

Category 2*: sequence variation is previously unreported and is of the type that is expected to cause the disorder
  • Variant is rare
  • Variant is predicted to disrupt reading frame but not damage protein function
OR
  • Variant is uncommon
  • Variant is predicted to disrupt reading frame and damage protein function

Category 3: sequence variation is previously unreported and is of the type which may or may not be causative of the disorder
  • Variant is rare
  • Variant is predicted to damage protein function with moderate confidence
OR
  • Variant is uncommon
  • Variant is predicted to damage protein function with high confidence

Category 4: sequence variation is previously unreported and is probably not causative of disease
  • Variant is rare
  • Variant is predicted to damage protein function with low confidence
  • Variant is predicted to damage regulatory function with high confidence
OR
  • Variant is uncommon
  • Variant is predicted to damage protein function with moderate confidence

Category 4*: sequence variation is previously unreported and is probably not causative of disease
  • Variant is rare
  • Variant is predicted to damage regulatory function with low confidence
OR
  • Variant is uncommon
  • Variant is predicted to damage protein function with low confidence

Category 5: sequence variation is previously reported and is a recognized neutral variant
  • Variant is uncommon
  • Variant is not predicted to damage protein function
OR
  • Variant is common

Category 6: sequence variation is previously reported and is associated with the disorder
  • Sequence variant is reported in the literature as associated with disease
  • Variant is common

If none of the above are met, "-~-~-" is reported in the ADVISER score column.

Scripps Genome ADVISER | Annotation and Distributed Variant Interpretation Server