Seeking Guidance on Relevant AlphaGenome Features for RNU4-2 Variant Interpretation

Community
1

Hi all,

We are working on variant interpretation for RNU4-2, a very small spliceosomal snRNA where pathogenic variants cluster within very short structural elements. Our current AlphaGenome-based model uses only five features and fails to correctly classify known ClinVar-pathogenic variants in this gene.

From the scoring script, the features we currently derive are:

  1. center_mask_atac (CenterMaskScorer on OutputType.ATAC)

  2. H3K4me3 (from OutputType.CHIP_HISTONE, histone_mark = “H3K4me3”)

  3. H3K27ac (from OutputType.CHIP_HISTONE, histone_mark = “H3K27ac”)

  4. gene_lfc (GeneMaskLFCScorer on OutputType.RNA_SEQ)

  5. splice (CenterMaskScorer on OutputType.SPLICE_SITES)

For a compact ncRNA like RNU4-2, are these modalities and scorers expected to carry meaningful signal?
And would you recommend additional AlphaGenome OutputTypes or scorer configurations that might better capture ncRNA-specific constraints or highly local structural effects?

Thanks!

2

Do you have any hypothesis on the mechanisms of the variants? AG can predict expression, splicing, chromatin, it can not predict missense variant or variant affect RNA structure.