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Integrate ClinVar Labels with AlphaMissense Pathogenicity Scores

Source: R/ClinVar.R
ClinVar.Rd

clinvar_data() loads ClinVar information from the supplemental table of the AlphaMissense [2023] paper.

clinvar_plot() integrates ClinVar classifications with AlphaMissense predicted scores derived from am_data("aa_substitutions") and returns a ggplot object for visualization.

Usage

clinvar_data(record = ALPHAMISSENSE_RECORD, bfc = BiocFileCache())

clinvar_plot(uniprotId, alphamissense_table, clinvar_table)

Arguments

record

character(1) Zenodo record for the AlphaMissense data resources.

bfc

an object returned by BiocFileCache() representing the location of the AlphaMissenseR database. The default is the 'global' BiocFileCache.

uniprotId

character() a valid UniProt accession identifier.

alphamissense_table

a table containing AlphaMissense predictions for protein variants. By default, the table is derived from am_data("aa_substitution"). Alternatively, a user-defined tibble::tbl_df or data.frame can be supplied.

clinvar_table

a table containing ClinVar information. By default, the table is derived from the supplemental data of the AlphaMissense paper. Alternatively, a user-defined tibble::tbl_df or data.frame can be supplied.

Value

clinvar_data() returns a tbl with 82872 rows and 5 variables:

  • variant_id: ClinVar variant identifier.

  • transcript_id: Ensembl transcript identifier.

  • protein_variant: UniProt accession:protein variant identifier.

  • AlphaMissense: AlphaMissense pathogenicity score.

  • label: Binary ClinVar class, either "benign" or "pathogenic".

clinvar_plot() returns a ggplot object which overlays ClinVar classifications onto AlphaMissense predicted scores. Blue, gray, and red colors represent pathogenicity classifications for "likely benign", "ambiguous", or "likely pathogenic", respectively. Large, bolded points are ClinVar variants colored according to their clinical classification, while smaller points in the background are AlphaMissense predictions.

Details

For clinvar_plot(), alphamissense_table columns must include:

  • uniprot_id: UniProt accession identifier.

  • protein_variant: variant identifier string, with protein position in the middle, and the reference and mutant amino acid residues to the left and right of the position, respectively.

  • am_class: AlphaMissense classification of either "benign", "ambiguous", or "pathogenic".

  • am_pathogenicity: AlphaMissense predicted score.

clinvar_table columns must include:

  • uniprot_id: UniProt accession identifier, matching alphamissense_table.

  • protein_variant: variant identifier string, matching alphamissense_table format.

  • cv_class: binary ClinVar classification of "benign" or "pathogenic".

References

Cheng et al., Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381, eadg7492. DOI:10.1126/science.adg7492.

Examples

clinvar_data()
#> # Source:   table<clinvar> [?? x 5]
#> # Database: DuckDB v1.1.1 [mtmorgan@Darwin 23.6.0:R 4.5.0//Users/mtmorgan/Library/Caches/org.R-project.R/R/BiocFileCache/121787f1dafbc_121787f1dafbc]
#>    variant_id           transcript_id     protein_variant AlphaMissense label 
#>    <chr>                <chr>             <chr>                   <dbl> <fct> 
#>  1 chr1_925969_C_T_hg38 ENST00000342066.8 Q96NU1:P10S            0.967  benign
#>  2 chr1_930165_G_A_hg38 ENST00000342066.8 Q96NU1:R28Q            0.663  benign
#>  3 chr1_930204_G_A_hg38 ENST00000342066.8 Q96NU1:R41Q            0.0866 benign
#>  4 chr1_930245_G_A_hg38 ENST00000342066.8 Q96NU1:D55N            0.134  benign
#>  5 chr1_930248_G_A_hg38 ENST00000342066.8 Q96NU1:G56S            0.100  benign
#>  6 chr1_930282_G_A_hg38 ENST00000342066.8 Q96NU1:R67Q            0.0635 benign
#>  7 chr1_930285_G_A_hg38 ENST00000342066.8 Q96NU1:R68Q            0.0629 benign
#>  8 chr1_930314_C_T_hg38 ENST00000342066.8 Q96NU1:H78Y            0.110  benign
#>  9 chr1_930320_C_T_hg38 ENST00000342066.8 Q96NU1:R80C            0.0918 benign
#> 10 chr1_931058_G_A_hg38 ENST00000342066.8 Q96NU1:V92M            0.196  benign
#> # ℹ more rows

alphamissense_table <- am_data("aa_substitutions")

clinvar_plot(
    uniprotId = "P37023",
    alphamissense_table = alphamissense_table
)
#> * [09:25:17][info] 'clinvar_table' not provided, using default ClinVar dataset in AlphaMissenseR package