The Regulatory Mendelian Mutation score for GRCh38.

Area of Science:

• Genomics
• Bioinformatics
• Human Genetics

Background:

• Rare Mendelian diseases necessitate prioritizing noncoding variants for diagnosis.
• Limited tools and annotations exist for the GRCh38 human genome build, hindering variant assessment.
• The noncoding genome is a growing focus in rare disease research.

Purpose of the Study:

• To update the Regulatory Mendelian Mutation (ReMM) score for the GRCh38 human genome build.
• To improve accessibility of variant pathogenicity scores through a website and API.
• To provide a robust tool for prioritizing noncoding variants in rare Mendelian diseases.

Main Methods:

• Retraining the ReMM score using features and variants from the GRCh38 genome build.
• Developing a website and API for variant score lookup and file scoring.
• Evaluating ReMM score performance on imbalanced datasets.

Main Results:

• The updated ReMM score demonstrates good performance on imbalanced data, comparable to the GRCh37 version.
• GRCh38 ReMM scores show high correlation with previous versions, with improved performance due to better feature coverage.
• The ReMM score outperformed other variation scores for noncoding mutation prioritization in imbalanced datasets.

Conclusions:

• The ReMM score is a valuable tool for prioritizing noncoding mutations in rare Mendelian diseases.
• The GRCh38 version and associated web tools enhance the utility and accessibility of ReMM scores.
• Availability of prescored genome files, UCSC genome browser tracks, and an API facilitates broader research application.