3/3 Our study also introduces a simple structural metric, SPDV, proposed as an orthogonal strategy to existing computational tools for aiding the diagnosis of RyR1-related diseases. If you are interested in applying this metric to other proteins, check out Lukas’ Colab notebook:
💻 edin.ac/40yke9l

2/3 If you work on MAVEs, or are a clinician curious about how strong MAVE or VEP evidence is in a gene, check out 𝚊𝚌𝚖𝚐𝚜𝚌𝚊𝚕𝚎𝚛. It calibrates functional scores to #ACMG/AMP standard, and you can run it via this Colab notebook:
💻 colab.research.google.com/github/badon...

Thanks also to @natcomms.nature.com for the smooth review process!

8/8 Our work raises many interesting questions, but I will leave you with one: when a disease can be caused by both dominant and recessive mutations, how can we predict which variants are pathogenic only in the recessive state?

7/8 Finally, we made it easy to compute mLOF for a set of missense variants: there is a user-friendly Google Colab notebook available for anyone to try.
💻 edin.ac/48Aysep

6/8 We also find that many genes can cause different diseases through different mechanisms. This carries an important message for therapeutic development, suggesting that different phenotypes of the same gene may need distinct treatment strategies.

5/8 Therefore, we applied mLOF to 2,837 phenotypes across 1,979 Mendelian disease genes. In dominant genes, nearly half of phenotypes appear to arise from non-LOF mechanisms.

4/8 Perhaps the most powerful validation of mLOF lies in multiplexed assays of variant effect #MAVE data. LOF, DN, GOF, and hyper-complementing variants identified by MAVEs are distinguished consistently and effectively by the mLOF score.

3/8 We introduce a protein structure-based missense LOF (mLOF) likelihood score, which predicts if mutations lead to LOF based on how much they cluster in structures and how energetically destabilising they are.

2/8 Knowledge of mechanisms is hugely important for treating genetic diseases: LOF mutations can usually be treated with gene replacement, but other mechanisms often require more targeted approaches.

Yes, if vaccines count as a discovery, I would add the Haber-Bosch process for producing ammonia, and by extension, fertiliser to feed the world.

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In the previous version, I found the functionality where hovering over the sequence highlighted the corresponding residue in the structure to be very useful. Any chance this could be brought back while keeping the `copy sequence` button?

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We are working to update the manuscript with additional analyses that support the use of as few as 10 pathogenic and benign labels.

Both the R package and the Colab will soon receive small updates that improve interpretability and score threshold determination.