Pathogenicity Calculator: Use case for new users
(Allele: NM_000169.2:c.639+919G>A)
Use Case for a new user: Overview
Step 1: Identify Allele
Step 2: Launch the Calculator
Step 3: Create evidence document and input evidence
Step 4: Calculate conclusions and examine reasoning
Step 5: Generate Summary Report
Step 6: Retrieve stored evidence,reasoning and assertion
Allele: NM_000169.2:c.639+919G>A
Allele: NM_000169.2:c.639+919G>A
Gene:GLA (alpha galactosidase)
Allele selected for curation in clinical sequencing and exploratory research (CSER)
Three groups curated the variant with PP1-Moderate,PS3, PS4, PVS1, PM4, PP1, PP5, PP3 tags, leading to 3 different conclusions per ACMG Guidelines:
Pathogenic, Likely Pathogenic, Uncertain Significance
Consensus curation agreed on the following evidence tags for Fabry disease: PS4, PVS1-Strong, PS3, PP1
In the present use case, these four evidence tags will be used for this allele to calculate a conclusion based on ACMG guidelines
Preferred browsers for the use-case
Google Chrome
Firefox
Safari
Calculator webpage
Step 1: Identify allele: Click on Start New Interpretation
Step 1: Identify allele: The allele search panel pops up
If working with new alleles or alleles that are not known to ClinGen Allele Registry, the registry may ask you to provide login, please provide your calculator credentials (login/password ), there. Once registered, please research the variant.
Step 1: Identify allele:
Search: NM_000169.2:c.639+919G>A
This term should be exact HGVS expression or CA identifiers. Some valid and invalid HGVS expressions are shown here with reason:
✓ NM_001127511.2:c.71C>T
✓ ENST00000507379.5:c.71C>T
✓ NM_181825.2:c.89A>G
✓ NC_000022.10:g.30000076A>G
Valid
Invalid
x NM_001127511:c.71C>T [No version of the reference sequence]
x APC:c.71C>T [APC is not sufficient to identify reference sequence]
x NM_181825.2(NF2):c.89A>G [Please don’t provide name of the gene in HGVS]
x NC_0000 22.10:g. 300000 76A>G [Please don’t include space in HGVS ]
x chr22:g.30000076A>G [chr22 is not a reference sequence]
Step 2: Launch the calculator
Click to interpret this variant
Some source that have information regarding this variant
Click on the red circle (with “-” sign) in
“Toggle Evidence” row
If you are a member of a group then you will see multiple columns here. One for each member.
Click create on the tab under your login
Provide information about condition and mode of inheritance
This initially provided condition and mode of inheritance is editable later using:
“Manage Evidence Docs” >> “Edit condition/Inheritance”
This is a type ahead functionality, just write few alphabets of disease, the interface will prompt you the disease names.
Click OK
Evidence document without any evidence tags
Click ACMG Table to see summary of Evidence tags published by ACMG/AMP in a new browser tab/window
Location of PS4, PS3, PP1 and downgraded PVS1 (PVS1-Strong)
Mouseover different cells to know possible tags in cell
Step 3: Create evidence
document and input
evidence: Turn PS4 tag on
Step 3: Create evidence
document and input
evidence: Turn PS4 tag on
Step 3: Create evidence
document and input
evidence: Turn PS4 tag on
Step 3: Create evidence
document and input
evidence: Turn PS4 tag on
Add link to pubmed article/external source reporting the data behind the tag
Click on the cell with PS4 tag
Step 3: Create evidence
document and input
evidence: Turn PS4 tag on
Select the row
Step 3: Create evidence
document and input
evidence: Turn PS4 tag on
Click Manage Link
Step 3: Create evidence
document and input
evidence: Turn PS4 tag on
Click add link
Step 3: Create evidence
document and input
evidence: Turn PS4 tag on
Enter the link to the PubMed article. Select “Supports” from the pull down menu in “Link Code” and put a comment about the article.
To add another link click “Add Link” again.
When finished putting external data links in click on “Save Links.
Step 3: Create evidence
document and input
evidence: Turn PVS1-
Strong tag ON
Step 3: Create evidence
document and input
evidence: Turn PVS1-
Strong tag ON
Create evidence
document and input
evidence: Turn PS3 tag
ON
Alternative add evidence tags
Create evidence
document and input
evidence: Turn PS3 tag
ON
After turning the tag on, add PubMed articles or other external source(s) for supporting the tag along with comments
Step 3: Create evidence
document and input
evidence: Turn PP1 tag
ON
Step 3: Create evidence
document and input
evidence: Turn PP1 tag
ON
Step 4: Conclusion and Reasoning
The conclusion reached is “Pathogenic”.
The rule that is satisfied is highlighted
next to the conclusion.
The rules that are not satisfied are also
listed below but are not highlighted.
For each rule that is not satisfied, the
number of missing evidence items is
listed.
By clicking on the rule that is not
satisfied, missing evidence items (grid
columns) are highlighted, helping identify
evidence tags that may lead to a
conclusion.
Step 5: Generate summary report of allele, evidence, assertion and reasoning
Step 5: Generate summary report of allele, evidence, assertion and reasoning
The report can be printed to the printer or as file for sharing
The links to articles are clickable.
The article and summary is generated based on data provided by user.
Step 6: Retrieve the stored evidence,reasoning and assertion
The created evidence document for allele (NM_000169.2:c.639+919G>A, CA021883) becomes available in the dashboard showing the assertion.
User can click on “1” to display variant and interpretations
Step 6: Retrieve the stored evidence,reasoning and assertion