---

type: allele_score
allele_score_mode: substitutions

table:
  filename: fordist_constraint_official_mpc_values_v2.txt.gz
  format: tabix

  # defined by score_type
  chrom:
    name: chrom
  pos_begin:
    name: pos
  pos_end:
    name: pos
  reference:
    name: ref
  alternative:
    name: alt

# score values
scores:
  - id: MPC
    name: MPC
    type: float
    desc: |
      Missense badness, PolyPhen-2, and Constraint.
      A deleteriousness prediction score for missense variants"
    large_values_desc: "more pathogenic"
    small_values_desc: "less pathogenic"
    histogram:
      type: number
      number_of_bins: 100
      view_range:
        min: 0.0
        max: 5.0
      y_log_scale: True


default_annotation:
  - source: MPC
    name: mpc

meta:
  summary: |

    MPC (Missense badness, PolyPhen-2, and Constraint) is a composite score that predicts the impact of missense variants.

  description: |

    A deleteriousness prediction score for missense variants based on regional
    missense constraint. The range of MPC score is 0 to 5. The larger the score, the
    more likely the variant is pathogenic. 
    
    Given increasing numbers of patients who are undergoing exome or genome
    sequencing, it is critical to establish tools and methods to interpret the
    impact of genetic variation. While the ability to predict deleteriousness
    for any given variant is limited, missense variants remain a particularly
    challenging class of variation to interpret, since they can have drastically
    different effects depending on both the precise location and specific
    amino acid substitution of the variant. In order to better evaluate
    missense variation, we leveraged the exome sequencing data of 60,706
    individuals from the Exome Aggregation Consortium (ExAC) dataset to
    identify sub-genic regions that are depleted of missense variation.
    We further used this depletion as part of a novel missense deleteriousness
    metric named MPC. We applied MPC to de novo missense variants and identified
    a category of de novo missense variants with the same impact on
    neurodevelopmental disorders as truncating mutations in intolerant
    genes, supporting the value of incorporating regional missense constraint
    in variant interpretation.

    Details see doi: http://dx.doi.org/10.1101/148353.

    TODO

    tabix -s 1 -b 2 -e 2 -f fordist_constraint_official_mpc_values_v2.txt.gz
  labels:
    reference_genome: hg19/genomes/GATK_ResourceBundle_5777_b37_phiX174
