Interpretation of variants by ACMG standards and guidelines

Extensive annotation is applied during our genomics analysis. Interpretation of genetic determinants of disease is based on many evidence sources. One important source of interpretation comes from the Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (Richards et al., 2015), full text at doi: 10.1038/gim.2015.30. The following tables are provided as they appear in the initial steps of our filtering protocol for the addition of ACMG-standardised labels to candidate causal variants.

Criteria for classifications

Caveats implementing filters

Implementing the guidelines for interpretation of annotation requires multiple programmatic steps. The number of individual caveat checks indicate the number of bioinformatic filter functions used. Unnumbered caveat checks indicate that only a single filter function is required during reference to annotation databases. However, each function depends on reference to either one or several evidence source databases (approximately 150 sources) which are not shown here.

For reference, alternative public implementations of ACMG guidelines can be found in (Li & Wang, 2017) and (Xavier et al., 2019); please note these tools have not implemented here nor is any assertion of their quality offered. Examples of effective variant filtering and expected candidate variant yield in studies of rare human disease are provided by (Pedersen et al., 2021).

References

1. Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., & others. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine, 17(5), 405–423.
2. Li, Q., & Wang, K. (2017). InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. The American Journal of Human Genetics, 100(2), 267–280.
3. Xavier, A., Scott, R. J., & Talseth-Palmer, B. A. (2019). TAPES: A tool for assessment and prioritisation in exome studies. PLoS Computational Biology, 15(10), e1007453.
4. Pedersen, B. S., Brown, J. M., Dashnow, H., Wallace, A. D., Velinder, M., Tristani-Firouzi, M., Schiffman, J. D., Tvrdik, T., Mao, R., Best, D. H., & others. (2021). Effective variant filtering and expected candidate variant yield in studies of rare human disease. NPJ Genomic Medicine, 6(1), 1–8.