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Non-coding variant interpretation using GeneTalk

Variants in noncoding regions are always difficult to interpret on a genomic level . In a recently published article in Human Mutation entitled

Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of HPMRS

we present an approach for filtering pathogenic nonconding variants and explain how to interpret the implications of the variants on protein level. We analysed the variants on RNA level by applying targeted gene panel sequencing on a cDNA library and sequenced all transcripts of the GPI anchor synthesis pathway.

When gDNA variant data is analysed the filter is set to identify variants in the coding regions, that have implications on the protein level. Contrariwise, when filtering cDNA variant data, mutations in noncoding regions provide valuable information about their pathogenicity. Variants that are found in remaining introns indicate that the transcript is not correctly spliced. By comparing the allelic balance between gDNA and cDNA data the regulation (miRNA-emdiated, nonsense mediate decay, or methylation) of expression of a transcript can be determined. In our example a rare 3’UTR variant led to the down regulation of a healthy allele resulting in a predominant expression of the mutant allele.

Using GeneTalk on variant data from cDNA sequencing pathogenic noncoding variants can be identified!