Document Type

Conference Paper/Presentation

Publication Date



Sabah Kadri PhD; Director of Bioinformatics, Ann & Robert H. Lurie Children’s Hospital, Assistant Professor of Pathology, Northwestern University

Kai Lee Yap, PhD FACMG; Director of Molecular Diagnostics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Assistant Professor of Pathology, Northwestern University


Dramatically expanding our ability for clinical genetic testing for inherited conditions and complex diseases such as cancer, next generation sequencing (NGS) technologies are allowing for rapid interrogation of thousands of genes and identification of millions of variants. Variant annotation, the process of assigning functional information to DNA variants based on the standardized Human Genome Variation Society (HGVS) nomenclature, is a fundamental challenge in the analysis of NGS data that has led to the development of many empirically based tools. In this study, we evaluated the performance of three variant annotation tools: Alamut Batch, ENSEMBL Variant Effect Predictor (VEP) and ANNOVAR, benchmarked by a manually curated ground truth set of 298 variants from the medical exome database at the Molecular Diagnostics Laboratory at Lurie Children’s Hospital. Of the three tools, VEP produces most accurate variant annotations (HGVS nomenclature for 297 of the 298 variants) due to usage of updated gene transcript versions within the algorithm. Alamut Batch called 296 of the 298 variants correctly; strikingly, ANNOVAR exhibited the greatest number of discrepancies (20 of the 298 variants, 93.3% concordance with ground truth set). Adoption of validated methods of variant annotation is critical in post analytical phases of clinical testing.



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.