Using computational approaches to enhance the interpretation of missense variants in the PAX6 gene

Nadya S. Andhika, Susmito Biswas, Claire Hardcastle, David Green, Simon C. Ramsden, Ewan Birney, Graeme C. Black, Panos Sergouniotis

Research output: Contribution to journalArticlepeer-review


The PAX6 gene encodes a highly-conserved transcription factor involved in eye
development. Heterozygous loss-of-function variants in PAX6 can cause a range of ophthalmic disorders including aniridia. A key molecular diagnostic challenge is that many PAX6 missense changes are presently classified as variants of uncertain
significance. While computational tools can be used to assess the effect of genetic
alterations, the accuracy of their predictions varies. Here, we evaluated and
optimised the performance of computational prediction tools in relation to PAX6 missense variants.

Through inspection of publicly available resources (including HGMD, ClinVar, LOVD and gnomAD), we identified 241 PAX6 missense variants that were used for model training and evaluation. The performance of ten commonly-used computational tools was assessed and a threshold optimization approach was utilized to determine optimal cut-off values. Validation studies were subsequently undertaken using PAX6 variants from a local database.

AlphaMissense, SIFT4G and REVEL emerged as the best-performing predictors; the
optimized thresholds of these tools were 0.967, 0.025, and 0.772, respectively.
Combining the prediction from these top-three tools resulted in lower performance compared to using AlphaMissense alone.

Tailoring the use of computational tools by employing optimized thresholds specific to PAX6 can enhance algorithmic performance. Our findings have implications for PAX6 variant interpretation in clinical settings.
Original languageEnglish
JournalEuropean Journal of Human Genetics
Publication statusPublished - 7 Jun 2024


  • Computational tools
  • PAX6
  • ; Missense variant
  • Variant interpretation
  • Variants of uncertain significance


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