Whether you're using the SEARCH application to look up a single structural variant, or you're analyzing a case with CNVs from your MY CASES tab, you're likely to end up in the Variant Interpretation hub for a deletion or a duplication. In this article, you'll find an overview of the segment interpretation tools provided by Franklin.
The Variant Interpretation hub:
How to get to the Variant Interpretation hub
There are two different ways to get to the Variant Interpretation hub for a certain variant:
From the SEARCH application, enter the variant details and click Search. It will take you directly to the Variant Interpretation page.
Franklin supports different nomenclatures, and you can check out the examples provided to find which one you prefer.
In addition, some optional questions will pop up, encouraging you to include case details and phenotypic information that might be relevant for the variant interpretation.
From the MY CASES application. If you have a structural variant in the workbench or variant list of your case, you can click on the tile to expand it and then select Full detail view or click on the cytobands to open the Variant Interpretation page.
Note: if you need help with case creation, check out this article.
ACMG/ClinGen Automated Classification
Franklin's AI-based algorithm provides an automated CNV classification based on the latest ACMG/ClinGen guidelines, leveraging evidence from a wide array of publicly available data sources and dedicated resources for structural variants curated by our team of cytogenetic specialists. If you'd like to know more about how Franklin computes this automated pathogenicity classification, check out this article.
In the Franklin ACMG Classification tab, you can find not only the overall classification result, but also the explanation for each rule that was met or unmet, and their corresponding score. To get more information about each specific criteria, you should click on the See Details button.
Franklin's classification engine will suggest a classification according to the latest guidelines. However, if you wish to modify the classification, feel free to click on the Edit button below the score of each rule. This will open a pop-up window where you can toggle between Met and Unmet for the criteria, and also adjust the points assigned to that piece of evidence.
Variant Assessment
The variant assessment tab presents a wide range of tools and visualizations that should help you analyze the clinical relevance of the variant. If you'd like to get a full list of the databases integrated into Franklin to source genetic evidence, head over to this article.
Clinical Summary
The Clinical Summary shows both the automated classification and the most relevant genes within the segment, which were found to have evidence of dosage sensitivity and are connected to conditions that may fit the case phenotypic information.
Region Viewer
Franklin’s embedded region viewer displays the area of the variant between the two blue lines. Here, Franklin presents the “Genes and Exons” track, the “Dosage Sensitivity” track with curated ClinGen evidence, and the "Organization Occurrences” track that provides us with insights taken from our own clinical database. This can be useful to assess how many times a segment observation has occurred in your organization within the region, alongside with their respective classification, and we can quickly obtain further details of the previous case, by clicking on the variant observation.
Organization Similar Variants
This widget displays variants with significant overlap specifically from your own organization's clinical data repository. If you'd like to know more, click on See details to further information and even access the previous case.
Community Similar Variants
This Community data-driven feature shows segments with significant overlap analyzed by other members of the Franklin Community. This tool provides immediate access to the community knowledge base and allows you to collaborate with fellow professionals.
Occurrences
The Occurences section presents evidence from population frequency databases, such as gnomAD and DGV. Click on See detailed occurrences to get more information regarding Subpopulations, when available.
Internal Occurrence
Here Franklin shows the occurrence of similar variants in your organization's database, specifying the number of samples with similar segments and the number of homozygotes.
References
Here Franklin presents submissions of similar CNVs available in other databases, such as ClinVar and DECIPHER. You may click on the link below the classification to learn more about this piece of evidence on their website.
Genes and Regions
Under the Genes and Regions tab, Franklin presents all genes that are encompassed within the segment. For each gene, it associates curated evidence such as dosage sensitivity and sensitivity to loss-of-function metrics, as well as the relationship with the case phenotypes. The related conditions are aggregated from multiple sources such as OMIM, Orphanet, Monarch, and other well-renowned public databases.
This list of genes and regions can be filtered by:
Type: Coding/Non-coding gene, region
Impact: Whole gene, exonic, intronic, etc.
Sensitivity: Evidence of Hapoinsufficiency/Triplosensitivity
Inheritance: Autosomal recessive/dominant, X-linked, Y-linked, etc.
Condition source: Monarch, OMIM, Ophanet, etc.
Genes: Each of the genes affected by the CNV
Associated Conditions
The Associated Conditions tab will present the list of conditions that may be caused by the queried variant. Using complex algorithms, and an abundance of annotated data for each variant from sources such as OMIM, Orphanet, GeneReviews, Diseases, and PubMed Franklin calculates and aggregates gene-disease correlations.
Each condition is represented by a tile, showing the condition name, the sources for the correlation evidence, the disease inheritance model, and the strength of the evidence linking the condition to the gene, as well as the matching phenotypes for the case.
By clicking on the arrow on the right, or anywhere in the tile, you can access the Condition page, where you find a brief summary of the disease, alongside all the phenotypes reported to be associated with the disease, and their occasionality (if available). Franklin will also link the condition entry to all well-known databases, such as OMIM, GENCC and Orphanet.
Publications
The Publications tab is powered by Franklin's powerful Natural Language Processing (NLP) AI-based algorithm. Here, the platform constantly examines large volumes of genomic literature and highlights the most relevant evidence for the specific case.
The dedicated search engine annotates publications based on genes, conditions, phenotypes, and specific variants, and provides a prioritized list of relevant publications based on biomarkers and phenotypic information. Users can filter the list according to a specific gene of interest and the date of publication.
If you'd like to learn more about this tool, head to Franklin's Publications engine article.
My Organization Assessments
Under this last tab, you can get insights from your organization's knowledge base. Here you are able to find the previous curated classifications of similar structural variants within your Franklin organization, alongside their interpretation text.