Fusion Variant Coordinates

Each Fusion Variant page has fields for coordinate display. This means that both the general Fusion bucket Variant and the exon specific (eX::eY) Fusion Variant forms have coordinates associated to them. For the exon specific Variant form, these coordinates demonstrate the exons that comprise each member of the gene fusion. For the generalized Fusion Variant, these are meant to be representative coordinates, e.g. the exons most often seen for the gene fusion.

Representative Coordinates for BCR::ABL1 Fusion Variant

Figure 1: Curated representative exons and coordinates are shown for the BCR::ABL1 general Fusion Variant

The coordinate fields shown on the Fusion Variant page are calculated automatically, using exon number information input by the curator. There are two coordinate tabs on the page, one for each partner gene, shown in the figure below. The first tab gives general information on the gene coordinates, including exon start and end, including the untranslated region (UTR) on each side of the gene fusion. The “Partner Exon Coordinates” tab gives information on the specific exons including exon start and stop coordinates, and the strand direction in which transcription occurs.

Fusion Variant Page Coordinate Fields

Figure 2: Fusion Variant coordinates (Shown here for the Fusion EML4::ALK Variant e20::e20) display genomic and exon coordinate information for both the 5' and 3' partners. Shown in this figure are the 5' partner fields. There are two tabs. The Genomic Coordinates tab gives general information including Reference Build, Ensembl version and transcript. Start and Stop fields in this tab indicate the start and end coordinates of the transcript, which include untranslated regions (UTRs). The 5' Partner Exon Coordinates tab shows specific information on the 5' gene exons, including exon numbers, Ensembl exon IDs, and importantly, Start, Stop, Strand, and Offset information. Start and Stop are determined by the exon boundaries including UTR. Strand shows gene transcription direction, and Offset is a positive or negative number, which starts at the gene boundary, indicating if part of the exon was removed by the fusion, or if part of the intron was added to the fusion.

An overall schema of how coordinates for Fusions in CIViC are prepared is shown below. Note the untranslated regions (UTRs) are included, and that the coordinate is calculated from the last DNA base in the given exon. Offsets are calculated from that position as shown in the figure.

Interpreting Fusion Coordinates

Figure 3: Fields in the Fusion Variant coordinate tables are filled out according to the scheme shown. For each partner gene, Start coordinate is always smaller than the Stop coordinate, regardless of strand orientation. Exon coordinates include untranslated regions (UTRs). The coordinate of the last base in the exon or UTR is used, and the Offset is counted from this base in a positive or negative direction.

Some key notes regarding coordinates for Fusions in CIViC:

• During curation, curators enter Ensembl transcript, exon numbers, strand, and offsets (if needed). Coordinates are automatically generated by CIViC.

• Both the “Fusion” bucket Variant, and the eX::eY Fusion Variant that specifies exons have the same coordinate fields. Often for bucket Variants of the “Fusion” type, multiple exon combinations occur, and often assays used such as FISH do not distinguish exon combinations. Therefore, for the bucket Variant, curation of exons is optional. If the curator wishes to add exons, then representative exons can be added, for instance using an exon combination that is frequently seen. If no representative exon combinations are apparent, then these fields can be left blank.