[PEER REVIEWED] GermVarX: An Automated Workflow for Joint Germline Variant Exploration in Whole-Exome Sequencing Cohorts v1

GermVarX is an open-source workflow for joint germline variant discovery and exploration in WES cohort studies. A key feature of GermVarX is its implementation of joint variant calling, enabling simultaneous genotyping of multiple samples to produce a single, high-confidence multi-sample VCF, optimized for downstream analyses. Implemented in Nextflow DSL2 with Docker, it supports fully automated execution, a modular architecture, and parallelized task execution across diverse computing environments, including workstations, HPC clusters, and cloud platforms. The workflow integrates two state-of-the-art variant callers—GATK HaplotypeCaller and DeepVariant—with joint genotyping performed via GATK or GLnexus. To increase reliability, GermVarX supports consensus generation between callers, coupled with sample- and cohort-level quality control, functional annotation using the Variant Effect Predictor (VEP), and unified reporting through MultiQC. In addition, it provides PLINK-compatible outputs, facilitating seamless integration with statistical and association analyses.