This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/humu.23427. This article is protected by copyright. All rights reserved. Inferring the Effect of Genomic Variation in the New Era of Genomics Samya Chakravorty 1 and Madhuri Hegde 1* 1 Department of Human Genetics, Emory University School of Medicine, Whitehead Biomedical Research Building Suite 301, 615 Michael Street NE, Atlanta, Georgia 30322, USA. * Corresponding author email: mhegde@emory.edu Grant Numbers: Muscular Dystrophy Association grant (418496), Jain Foundation grant (00072405) to Dr. Madhuri Hegde Abstract Accurate and detailed understanding of the effects of variants in the coding and non-coding regions of the genome is the next big challenge in the new genomic era of personalized medicine, especially to tackle newer findings of genetic and phenotypic heterogeneity of diseases. This is necessary to resolve the gene-variant-disease relationship, the pathogenic variant spectrum of genes, pathogenic variants with variable clinical consequences, and multi-loci diseases. In turn, this will facilitate patient recruitment for relevant clinical trials. In this review, we describe the trends in research at the intersection of basic and clinical genomics aiming to a) overcome molecular diagnostic challenges and increase the clinical utility of next-generation sequencing (NGS) platforms, b) elucidate variants associated with disease, c) determine overall genomic complexity including epistasis, complex inheritance patterns such as “synergistic heterozygosity”, digenic/multigenic inheritance, modifier effect, and rare variant load. We describe the newly emerging field of integrated functional