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Frequency Conservation Score (FCS): the power of conservation and allele frequency for variant pathogenic prediction

View ORCID ProfileJose Luis Cabrera Alarcon, Jose Antonio Enriquez, Fátima Sánchez-Cabo
doi: https://doi.org/10.1101/805051
Jose Luis Cabrera Alarcon
1Bioinformatics Unit Centro Nacional de Investigaciones Cardiovasculares (CNIC)
2GENOPHOS, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
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  • ORCID record for Jose Luis Cabrera Alarcon
  • For correspondence: jlcabreraa@cnic.es fscabo@cnic.es
Jose Antonio Enriquez
2GENOPHOS, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
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Fátima Sánchez-Cabo
1Bioinformatics Unit Centro Nacional de Investigaciones Cardiovasculares (CNIC)
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  • For correspondence: jlcabreraa@cnic.es fscabo@cnic.es
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ABSTRACT

Background Prediction of pathogenic variants is one of the biggest challenges for researchers and clinicians in the time of next-generation sequencing technologies. Stratification of individuals based on truly pathogenic variants might lead to improved, personalized treatments.

Results We present Frequency Conservation Score (FCS) and Frequency Conservation Score for Mitochondrial DNA (FCSMt) two methods for the detection of pathogenic single nucleotide variants in nuclear and mitochondrial DNA, respectively. These scores are based in a random forest model trained over a set of potentially relevant predictors: (i) conservation scores (PhastCons and phyloP); (ii) locus variability at each genomic position built from gnomAD database and (iii) physicochemical distance for amino acids substitutions and the impact/consequence over the canonical transcript. FCS showed an AUC of 98% for deleteriousness in an independent validation dataset, outperforming other scores such as metaLR, metaSVM, REVEL, DANN, CADD, SIFT, PROVEAN or FATHMM-MKL. Moreover, FCSMt presented an AUC=0.92 for pathogenic mitochondrial SNVs detection. The tool is available at http://bioinfo.cnic.es/FCS

Conclusions FCS and FCS-Mt improve pathogenic mutation detection, allowing the prioritization of relevant variants in Whole Exome and Whole Genome Sequencing Analysis.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 15, 2019.
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Frequency Conservation Score (FCS): the power of conservation and allele frequency for variant pathogenic prediction
Jose Luis Cabrera Alarcon, Jose Antonio Enriquez, Fátima Sánchez-Cabo
bioRxiv 805051; doi: https://doi.org/10.1101/805051
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Frequency Conservation Score (FCS): the power of conservation and allele frequency for variant pathogenic prediction
Jose Luis Cabrera Alarcon, Jose Antonio Enriquez, Fátima Sánchez-Cabo
bioRxiv 805051; doi: https://doi.org/10.1101/805051

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