VCF.Filter: interactive prioritization of disease-linked genetic variants from sequencing data

Abstract

Next generation sequencing is widely used to link genetic variants to diseases, and it has massively accelerated the diagnosis and characterization of rare genetic diseases. After initial bioinformatic data processing, the interactive analysis of genome, exome, and panel sequencing data typically starts from lists of genetic variants in VCF format. Medical geneticists filter and annotate these lists to identify variants that may be relevant for the disease under investigation, or to select variants that are reported in a clinical diagnostics setting. We developed VCF.Filter to facilitate the search for disease-linked variants, providing a standalone Java program with a user-friendly interface for interactive variant filtering and annotation. VCF.Filter allows the user to define a broad range of filtering criteria through a graphical interface. Common workflows such as trio analysis and cohort-based filtering are pre-configured, and more complex analyses can be performed using VCF.Filter's support for custom annotations and filtering criteria. All filtering is documented in the results file, thus providing traceability of the interactive variant prioritization. VCF.Filter is an open source tool that is freely and openly available at http://vcffilter.rarediseases.at.

Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation

“…6 Pik3cg -/mice display reduced NK-cell numbers, defective NK-cell development and consequently, decreased cytotoxicity. 3 We also observed reduced frequency, absolute counts and degranulation of patient NK cells compared to cells derived from the mother and HD (Table 1, Fig. S1B-C).…”

“…Genomes, gnomAD, and dbSNP build 149. After further filtering steps for nonsense, missense, and splice-site variants using VCF.Filter software, 3 an internal database was used to filter for recurrent variants. Moreover, variants were prioritized using tools, such as SIFT, Polyphen-2 and the combined annotation dependent depletion (CADD) score, 4,5 that predict the deleteriousness of a present variant.…”

“…Studies on PI3K in human disease have highlighted PI3K-gamma (PI3Kγ) as an appealing drug target for treatment of human disorders. 2 Murine PI3Kγ studies showed its importance in regulating innate immune functions and development [3][4] and activation of T cells, 5 revealing its role in controlling inflammation. 4 However, its role in the human immune system and diseases remains to be investigated.…”

“…The impaired NK cell compartment may have contributed to the observed clinical HLH-like phenotype. 3 We further hypothesized that a defect in PI3Kγ signaling would affect TCR-driven activation of T cells. 7 Patient T-cell subsets were comparable to HD (Table S2).…”

VCF‐Server: A web‐based visualization tool for high‐throughput variant data mining and management

“…Experienced researchers might prefer to keep their in-house annotations for downstream analysis. Other tools including VCF-Miner (Hart et al, 2016), VCF.Filter (Muller et al, 2017), myVCF (Pietrelli & Valenti, 2017), and BrowseVCF (Salatino & Ramraj, 2017) skip the annotation step and allow users to filter variants with their in-house annotations in the VCF. However, in most cases, they require users to annotate the VCF with other annotation tools before querying and filtering variants.…”