OMIM® Integration for VarSome Clinical and VarSome 11.5

Summary of the key features

• Diseases and phenotypes have been merged and we now only refer to phenotypes.
• Filter suggested phenotypes by source when typing a term in the Phenotypes box.
• Select either MONDO, OMIM® or HPO terms or just  OMIM® in phenotype matching of VarSome Clinical (displayed in the phenotype column).
• ACMG classification can now use OMIM® or all data sources for mode of inheritance of a gene.

General update: diseases are now merged into phenotypes in all our platforms

Phenotypes and diseases have been merged into phenotypes in VarSome and VarSome Clinical 11.5. You can enter diseases and phenotypes using the 'Phenotypes box':

To select the phenotypes of interest, start typing the term and select the phenotypes from the dropdown list. Phenotypes shown in the dropdown list can be limited based on their source. When selecting 'All' you will get terms from HPO, MONDO and OMIM® databases:

When selecting 'Only OMIM®', the dropdown terms will be retrieved solely from the OMIM® database:

VarSome

The merging of phenotypes and diseases affects the following menus of VarSome:

Optional sample information (germline queries)

Classify this variant

Link a publication

How phenotypes affect the ACMG classification in VarSome

The provided phenotypes (1) are used in combination with the additional information given in the optional sample information such as inheritance (2), family members affected (3) and family segregation (4). This information is used to evaluate the PP1, BS4, PS2, PM6 rules:

For example, we have a splicing variant in the gene PAX4 (chr7:127251731:CT:T) and the ACMG score gives us a Likely Pathogenic verdict. However, if we query this variant, adding information in the optional sample information such as 'Type 2 Diabetes Mellitus' as OMIM® phenotype and 'Yes' as 'Family Segregation', the rule PP1 will fire increasing the ACMG score:

PP1: cosegregation with phenotype in multiple affected family members in gene PAX4 which is associated with Diabetes Mellitus, Ketosis-Prone and Type 2 Diabetes Mellitus, according to GenCC, Mondo and OMIM®.

With PP1 triggered, this variant now reaches a Pathogenic verdict.

VarSome Clinical

Phenotypes and diseases have also been merged in VarSome Clinical similarly to VarSome and this affects the following features:

• Phenotype matching
• Gene lists

Additionally, the VarSome Clinical users can now decide which sources to use to get the mode of inheritance of a gene, which directly impacts on ACMG classification. 

Sources to be used for inheritance (affects ACMG classification)

Some of the rules (PM2, BS2, BP1) implemented in the automated ACMG classifier depend on the mode of inheritance of the given gene. In VarSome Clinical, it is now possible to decide which sources we want to use to get the mode of inheritance of a gene for the ACMG annotation when launching an analysis.

There are two options:

1. When selecting 'All', we will use different sources to assess the mode of inheritance: OMIM®, CGD, GenCC, Gene2Phenotype and Clingen disease validity. We consider the information from all of these sources meaning that, for example, if CGD says a gene is AD (autosomal dominant) and OMIM® says AR (autosomal recessive), the mode of inheritance will be AD/AR. We take the confidence level into consideration as well. Both CGD and OMIM® sources are considered as definitive (strongest evidence). However, in OMIM® we do not use the mode of inheritance if the relationship between the gene and the phenotype is provisional (labeled with a question mark at the beginning of the phenotype name).
   As for the rest of sources (GenCC, Gene2Phenotype and Clingen), we use the confidence level (e.g. Strong, Definitive, Supporting, Disputed Evidence), to assess the mode of inheritance, and lower confidence level entries will have lower strength in the final inheritance selection.
2. If 'only OMIM®' has been selected, the classifier will only use OMIM® to get the mode of inheritance.

In the case where we can’t find any information about the mode of inheritance of a gene in any of the aforementioned databases, we fall back to Domino, which is a tool for assessing the probability for a gene to harbor dominant changes.

Example of annotation using 'All' or 'Only OMIM®' as phenotype sources for ACMG inheritance

For example, a sample is annotated in VarSome Clinical and it contains variant(s) falling in the PMS2 gene:

Case 1. The user selects “All” as Phenotype sources to be used in ACMG mode of inheritance:

The mode of inheritance will be AD/AR because it is based on gene information from CGD, ClinGen Disease Validity, GenCC, Mondo, OMIM® and gene2phenotype.

Case 2. The user selects 'Only OMIM®' as Phenotype sources to be used in ACMG mode of inheritance:

The PMS2 mode of inheritance will be AR because only OMIM was used to assess this mode of inheritance. 

As a consequence, PM2, BS2 and BP1 rules may change between both modes of annotation because the ACMG implementation uses different thresholds to evaluate these rules depending on the mode of inheritance. 

Phenotype matching

VarSome Clinical users can attach phenotypes to germline samples. When provided, a new column in the variant table (Phenotypes) is displayed showing the number of associations between the genes and the phenotypes provided. Consistently to our VarSome platform, we have also merged diseases into phenotypes so the users can now attach phenotypes (using HPO terms like before) and diseases (using MONDO and OMIM terms). 

Number of associations of the given phenotypes to the gene can be found in the Phenotypes column of the variant table. By hovering over the number, you can see which of the phenotypes provided are associated with the gene. 

Gene lists from phenotypes

It is possible to create gene lists from phenotypes using HPO, MONDO and/or OMIM®.

Further Information and Support

Not already a VarSome Premium, VarSome API or VarSome Clinical user? Get in touch and ask for a free trial.

As ever we hope you find these changes and improvements helpful, we’d love to hear any suggestions you may have, support is available as usual from support@varsome.com

- The VarSome Team