Align-GVGD

Align-GVGD predicts the functional impact of missense substitutions by combining biophysical properties of amino acids with protein multiple sequence alignments and Grantham-derived metrics to classify variants from deleterious to neutral.

Key Features:

• Integration of biophysical characteristics: Uses biophysical properties of amino acids and evolutionary conservation in protein MSAs to assess missense substitutions.
• Grantham-based scoring (A-GVGD): Extends the Grantham difference approach by computing Grantham Variation (GV) and Grantham Deviation (GD) to score substitutions against observed positional variation.
• Simultaneous multiple comparisons: Performs simultaneous multiple comparisons across alignment positions to provide context-aware classification of mutation impact.

Scientific Applications:

• Hereditary cancer variant classification (BRCA1, BRCA2): Classifies missense substitutions in BRCA1 and BRCA2 to inform interpretation of variants detected in genetic testing.
• TP53 functional prediction: Assesses biochemical distance of mutant amino acids using GV and GD to predict effects such as changes in TP53 transactivation activity.
• Clinical interpretation of unclassified variants: Aids classification of unclassified missense variants as neutral or deleterious to support variant interpretation.

Methodology:

Computes Grantham Variation (GV) and Grantham Deviation (GD) from protein MSAs; combines GV and GD using the Align-GVGD scoring method to predict functional consequences of missense substitutions; validates predictions against experimental assays (e.g., yeast transactivation assays) and compares results with tools such as SIFT and Dayhoff classification.