User manual

Author: Da (Kevin) Kuang

Last update on: 2020-10-22

Introduction

This repo contains code to:

1. Extract missense variants that had been observed in "clinical testing" (as opposed to "literature only") in ClinVar.

2. Calculate movability and reappearance parameters using the aggregated and capped Invitae variant counts.

3. Apply the movability and reappearance parameters to ClinVar genes, calculating their movability- and reappearance-weighted impact score (MARWIS), as well as their difficulty-adjusted impact score (DAIS).

4. Rank ClinVar genes based on:

   1. Unique number of VUS in ClinVar,
   2. Mobability- and Reappearance-weighted Impact Score (MARWIS), and
   3. Difficulty-ajusted Impact Score (DAIS).

Selection Criteria

The following selection criteria were applied:

1. Missense variants,

2. Variants classified to have uncertain significance (i.e. VUS), and

3. Variants that are collected through clinical testing and not through literature curation only.

Getting started

Download ClinVar data set

Please note: if filtered_variants.csv and missense_variants.csv files exist, the filtering process will be skipped.

Download the variant_summary.txt.gz and submission_summary.txt.gz files from the NCBI ClinVar FTP Site.

Please refer to this file for headers of both files.

Unzip downloaded files and leave the text files in the root directory of this repo.

Please make sure the plain text files are named as variant_summary.txt and submission_summary.txt.

Install packacges

In order to run the scripts below, you need to install these R packages:

data.table
stringr

Rank genes by unique ClinVar variants

Script: rankClinVarGenes.R

You may run the script by source()-ing it to an interactive R session or by executing the following command:

Rscript rankClinVarGenes.R

Two CSV files are needed as input:

1. invitae_variant_count.csv: aggregated per-gene level variant counts where the occurrence of each variant was capped at 7 (the same capping threshold used and documented in the manuscript).

2. gene_length.csv: protein-coding gene's proten length (i.e. number of amino acids) based on the canonical isoform according the the Ensembl database.

Three CSV files may be generated as output:

1. missense_variants.csv: missense ClinVar variants. This file will only be generated if it doesn't already exist.

2. filtered_variants.csv: ClinVar variants that passed all filtering criteria. This file will only be generated if it doesn't already exist.

3. ranked_clinvar_genes.csv: ranked ClinVar genes.

Header description for the final output file ranked_clinvar_genes.csv:

Header	Description
hgnc_id	HGNC ID
gene	Gene symbol
clinvar_missense_vus	Number of unique missesne VUS in ClinVar database
missense_vus_unique	Number of unique missesne VUS in Invitae database
missense_vus_movable_unique	Number of unique movable missesne VUS in Invitae database
missense_vus_observed	Number of occurance of missesne VUS in Invitae database
missense_vus_movable_observed	Number of occurance of movable missesne VUS in Invitae database
from_invitae	Whether the gene was included both in Invitaea and ClinVar database. If FALSE, the gene was only included in ClinVar database
missense_vus_movability_fraction	Fraction of unique missense VUS that are movable in Invitae database
missense_vus_occurance_per_variant	Average number of occurance of missense VUS in Invitiae database
weighted_movability_fraction	Weighted fraction of unique missense VUS that are movable in Invitae database; see Equation (2) in Section 2.4 of the manuscript
weighted_occurance_per_variant	Weighted average number of occurance of missense VUS in Invitiae database; see Equation (4) in Section 2.4 of the manuscript
marwis	Movability- and reappearance-weighted impact score; see Equation (6) in Section 2.4 of the manuscript
aa_length	protein-coding gene's proten length (i.e. number of amino acids) based on the canonical isoform according the the Ensembl database
dais	Difficulty-adjusted impact score; see Equation (7) in Section 2.5 of the manuscript
rank_by_clinvar_vus	Rank by number of unique missense VUS in ClinVar database
rank_by_marwis	Rank by MARWIS
rank_dais	Rank by DAIS

LICENSE

MIT

Copyright 2020 Kevin Kuang

Permission is hereby granted, free of charge, to any person obtaining a copy of this software and associated documentation files (the "Software"), to deal in the Software without restriction, including without limitation the rights to use, copy, modify, merge, publish, distribute, sublicense, and/or sell copies of the Software, and to permit persons to whom the Software is furnished to do so, subject to the following conditions:

The above copyright notice and this permission notice shall be included in all copies or substantial portions of the Software.

THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALL THE AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER DEALINGS IN THE SOFTWARE.