Variant Summary

In both the Shortlist tabs and Filter view, each variant is listed with a summary display, grouping the most crucial annotations. To explore more detailed annotations on the variant, the Variant card can be opened.

SV/CNV summary annotations

The following annotations are displayed in the summary display:

Gene annotation: The summary display shows the gene name of the gene for which the disorder annotation is considered most relevant for the input phenotype. If multiple genes are involved in the SV/CNV, the summary display also indicates the number of genes affected by the variant.

Location: Below the gene name, the chromosomal location of the event is indicated, as extracted from the input file. The dropdown menu allows to open the event in other genome browsers, Alamut or IGV.

Size: Below the chromosomal location of the SV/CNV, the size of the variant is indicated.

SV type: SV type is indicated in a separate column. Supported types in Moon are Deletions, Duplications, Insertions, Inversions, and Breakends. For deletions and duplications, the copy number (CN) is indicated below the SV type. The CN is directly extracted from the VCF if provided as input. Otherwise, it is arbitrarily set by Moon based on the type of the variation and expected reference copy number for the indicated genotype in the VCF.

Disorder name with link to OMIM/PubMed. The summary display only shows the single-gene disorder with the best match based on concordance between with known associated phenotypes and inputted clinical features. However, if a deletion or duplication overlaps with a known ClinGen dosage sensitive region (> 1 bp overlap required), the disorder name will be replaced by the name of the ClinGen dosage sensitive region (with link to ClinGen), and an indication of the overlap between the SV and the region (with link to the SV genome browser). The overlap is described as “intersecting”, “contained in” or “encompassing” as shown below.

Variant card

In both the Shortlist and Filter view, detailed and extended annotations on each variant are provided in a variant card. This variant card can be displayed by clicking the Info icon, which is available at the right hand side of a variant summary display.

Variant card annotations for SV/CNVs are the following.

General variant info

Gene annotation: Similar to the summary display, the variant card shows the gene name of the gene for which the disorder annotation is considered most relevant for the input phenotype and the total number of genes affected by the variant.

Size: Below the chromosomal location of the SV/CNV, an indication of the size of the variant will be displayed.

SV type: SV type is indicated at the top right of the variant card. For deletions and duplications, the copy number (CN) is indicated below the SV type. This CN is either directly extracted from the VCF if provided as input. Otherwise, it is arbitrarily set by Moon based on the type of the variation and expected reference copy number for the indicated genotype in the VCF.

Segregation

This section shows a pedigree for the analysed family configuration. The copy number (for DEL or DUP) or SV type (for BND, INS, INV) of included family members is displayed with the reference in black and the alternate in red. Affected family members are indicated with a filled symbol in the pedigree. Presence of positive consanguinity is also indicated, as inputted on the Patient info screen.

Disorder

The Disorder section displays the corresponding gene-specific disorders with link to OMIM/PubMed, and, if a deletion or duplication overlaps (> 1bp) with a known ClinGen dosage sensitive region, this overlapping CNV syndrome is also displayed. This section also includes the HPO checklist reflecting the overlap of input HPO terms with any of the disorders annotated for genes overlapping the variant in question. If a SV/CNV is in compound heterozygosity with a SNV, it is also indicated here.

For SV/CNVs overlapping multiple genes, the Disorder section shows the five disorders with the best match based on concordance between known disorder-associated phenotypes and the inputted clinical features. For each of these disorders, the variant card also indicates the inheritance pattern.

For SV/CNVs overlapping ClinGen regions, an indication of the overlap between the SV and the region (with link to the SV genome browser) is displayed. The overlap is described as “encompassing”, “contained in”, or “intersecting” (see scheme above).

In the HPO checklists, it is eg. possible that some HPO terms are checked based on overlap with disorder A, while other HPO terms in the same checklist are checked based on disorder B.

Chromosomal region

Overview of the disease-associated genes affected by the variant. Clicking the chromosomal region or the "Expand" icon opens the Moon SV/CNV genome browser, for easy exploration of all genes within and surrounding a SV/CNV variant.

Frequency

This section shows the gnomAD SV frequency for duplications and deletions, with indication of the number of homozygotes, heterozygotes and hemizygotes in this database. Additionally, the population allele frequencies from DGV Gold standard are also shown for deletions and duplications. For each DEL/DUP, the DEL/DUP with the highest population frequency in the considered database, that completely comprises the one in the sample or has the same gene content, is annotated.

Comments

At the bottom of the variant card, a text box is provided to add a comment to the variant. Double clicking your text allows text formatting and adding links. Details on who added the comment and when, are added upon saving. The comment can be easily removed by the person who added it, by clicking the trash icon.

Comments are visible to all members in the lab account. Comments will also be shown in other samples if a similar SV is present, with reference to the sample in which the Comment was originally added.