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American College of Medical Geneticists (ACMG) Variant Classification

Variant classification is the final stage of variant characterization. Classification includes assigning an interpretive category representing clinical significance to each variant. 

ACMG categories

The ACMG categories rely heavily on the identification of novel vs. known variants which implies comparison to external variation databases. RUNES currently uses HGMD and dbSNP to fulfill this role, though the current state of available databases limits their utility. These existing databases are incomplete (do not contain many variants), or can contain misannotations (incorrect identification of variant) or misassociations (association of common polymorphisms to disease) (Bell et. al).

Database enhancement

The initial version of RUNES is unable to categorize any variants as Category 5 or Category 6, meaning that most novel variants without clear pathogenicity will end up as Category 4. It is expected that as these existing resources improve or as additional clinical grade databases become available this categorization will be updated to include these categories.

Variant classifications

Every variant will receive a classification. RUNES uses categories recommended by the American College of Medical Geneticists - these are listed along with the criteria used for including a variant in each category:

Category Description Criteria


Previously reported, recognized cause of the disorder

HGMD variant type of 'Disease Mutant' dbSNP Snp Clinical Significance of 'pathogenic'


Novel, of a type expected to cause the disorder

loss of initiation

premature stop codon

disruption of stop codon

whole transcript deletion

frameshifting in/del

disruption of splicing through deletion causing CDS/intron fusion overlap with splice donor or acceptor sites


Novel, may or may not be causal

non-synonymous substitution

in-frame in/del

disruption of polypyrimidine tract

overlap with 5' exonic, 5' flank or 3' exonic splice contexts


Novel, probably not causal of disease

all variants of categories 1-3

synonymous AA changes

overlap with 5' intronic or 3' flank splice contexts pyrimidone

substitutions in polypyrimidine tract, other intronic variants

dbSNP GMAF of greater than 0.02


Known neutral variant

not used


Not known/expected to cause of disease but associated with clinical presentation

not used