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bioRxiv · 10.1101/2024.10.07.616631

Enhancing the annotation of small ORF-altering variants using MORFEE: introducing MORFEEdb, a comprehensive catalog of SNVs affecting upstream ORFs in human 5'UTRs

Meguerditchian, C.·Baux, D.·Ludwig, T. E.·Genin, E.·TREGOUET, D.-A.·Soukarieh, O.
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Abstract

Non-canonical small Open Reading Frames (sORFs) are among main regulators of gene expression. The most studied ones are upstream ORFs (upORFs) located in the 5UTR of coding genes. Internal ORFs (intORFs) in the coding sequence and downstream ORFs (dORFs) in the 3UTR have received less attention. Different bioinformatics tools permit to predict single nucleotide variants (SNVs) altering upORFs, mainly those creating AUGs or deleting stop codons, but no tool predict variants altering non-canonical translation initiation sites and those altering intORFs or dORFs. We propose an upgrade of our MORFEE bioinformatics tool to identify SNVs that may alter all types of sORFs in coding transcripts from a VCF file. Moreover, we generate an exhaustive catalog, named MORFEEdb, reporting all possible SNVs altering existing upORFs or creating new ones in human transcripts and provide an R script for visualizing the results. MORFEEdb has been implemented in the public platform Mobidetails. Finally, the annotation of ClinVar variants with MORFEE reveals that more than 45% of UTR-SNVs can alter upORFs or dORFs. In conclusion, MORFEE and MORFEEdb have the potential to improve the molecular diagnosis of rare human diseases and to facilitate the identification of functional variants from genome-wide association studies of complex traits.

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Meguerditchian, C., Baux, D., Ludwig, T. E., Genin, E., TREGOUET, D.-A., Soukarieh, O.. 2024-10-10. Enhancing the annotation of small ORF-altering variants using MORFEE: introducing MORFEEdb, a comprehensive catalog of SNVs affecting upstream ORFs in human 5'UTRs. https://doi.org/10.1101/2024.10.07.616631

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