Large CNVs and regions of homozygosity (ROH) can affect multiple genes.
The list contains two types of tiles - gene tiles and region tiles:
Gene tile
Gene tiles represent genes that intersect the variant borders.
At the upper side of the tile, you can find the gene name, with indication about the areas of the gene that were affected by the variant (e.g. whole gene). Below it you can find the transcript ID and the inheritance models associated with the gene.
To the right, summary statistics provide quick insights into:
Number of associated conditions that are associated with the gene (with a "See all" link)
Number of relevant publications associated with the gene (also with a "See all" link).
In the central panel, you find detailed scores related to gene dosage sensitivity and loss-of-function intolerance:
ClinGen Haploinsufficiency score, based on Clingen Dosage Sensitivity Map, with a link to ClinGen score details page. Genes with strong evidence for haploinsufficiency (HI) are likely to be sensitive to copy-number reduction. Detail explanation about the different values for the dosage-sensitivity score can be found here.
ClinGen Triplosensitivity score, based on Clingen Dosage Sensitivity Map, with a link to ClinGen score details page. Genes with evidence for triplosensitivity (TS) are likely to be sensitive to copy-number amplification. Detail explanation about the different values for the dosage-sensitivity score can be found here.
Calculated LOF score
Decipher HI score
pLI
o\e LOF (observed/expected LOF variants ratio)
Each score is color-coded to visually indicate strength of evidence or constraint. If a value is not available, it will be displayed as N/A to indicate that the information is currently missing.
At the bottom, the tile lists the top conditions that are associated with the gene, with conditions with inheritance mode and quick-access links to external relevant databases.
Clicking on the tile itself or the arrow in the right will expand the tile to show a summary about the gene and its role.
Region tile
The Clingen Dosage Map also lists pathogenic CNV regions. If such regions are encompassed completely within the variant borders, they appear in the Genes and Regions as a region tile (example below):
At the top-left side of the Region tile, instead of a gene name and transcript, you’ll see the cytogenetic location along with its genomic coordinates.
Below that, dosage sensitivity information is provided:
ClinGen Haploinsufficiency score, based on Clingen Dosage Sensitivity Map, with a link to ClinGen score details page.
ClinGen Triplosensitivity score, based on Clingen Dosage Sensitivity Map, with a link to ClinGen score details page.
Each score is color-coded to visually indicate strength of evidence or constraint. If a value is not available, it will be displayed as N/A to indicate that the information is currently missing.
Filter and sort
In the case of a large variant that affects many genes and regions, you can filter the list using the filters at the top of the page:
Type - filter coding genes, non-coding genes and/or regions
Impact - filter by the variant impact on the gene
Sensitivity - filter genes that have Clingen HI or TS scores
Inheritance - filter by the associated inheritance model
Condition source - filter genes that have associated conditions based on a specific source, such as OMIM or HPO.
Genes - filter specific genes
The list can be sorted using the “Sort by” parameters on the top left corner of the page, by Gene name, Haploinsufficiency score or Triplosensitivity score.
Adding phenotypes
Inputting your case phenotype brings up the genes with associated conditions that match your phenotype search. Phenotypes from your list that match the genes will be listed at the bottom of the gene tile, and the strength of the connection between the gene and the phenotypes is indicated by the gauge on the bottom-right corner.