Seqr behaviour with respect to "No Call" variants

[bellmartin]

Hi ,

It would be great to get some information/ feedback on the behaviour of seqr with respect to "No Call" variants .

When a variant can not be called ( for a variety of reasons), it is labelled as ./. within the vcf. Seqr interprets this as a "No Call", as it should, and you can see that in the seqr display.

What I am interested in, is the behaviour of the seqr searches when there is a "No Call" variant in a family.

Example" Proband : het, Mother : ref, Father : No Call

In the example above, the probands het does not come up in a de novo search due to the father having a "No call". Although it may have been paternally inherited, it may also be a true de novo event.
What the outcome ends up being is that any variant where a parent has a No Call at that position does not get returned in standard searches and therefore is missed. It is an understandable result, but as we have missed pathogenic variants due to this, so we would rather "No Call" is not used to filter variants out, but rather treated as a blank/ no value.

To get the example variant above returned in a seqr search, you need to set the parent with the "no call "in the inheritance filters to "?" and leave the allele count blank

This will allow the variant to be return, but it also allows all paternally inherited variants to be returned, therefore not a valid work around for this issue.

Questions

1. How are "No Call" variants recorded in the backend ( and how does that reflect how these variants are treated in the standard searches) ?
2. Is it possible to change how "No Call" variants are treated either in how they are recorded in the backend or at the search parameter stage so these type of variants can come through in standard searches ? By this I mean that the "No call" is treated as blank/ no value and not used by the inheritance filters to filter these variants out? We have our own instance of seqr - so with more understanding around this issue we could potentially implement our own changes either at the vcf level or search search parameters.

My overall philosophy for variants with a "No Call" is I want to be able to see them in the search results, so I can decide if they are worth investigating further. I can't chase what I don't know exists.

Thanks for any information you are able to provide around this topic! It is greatly appreciated
Katrina

[hanars]

Hi Katrina,

In answer to your questions:

1. In the backend these calls are represented with hail's "missing" value
2. It is not possible using the currently supported seqr functionality. Your workaround for toggling the affected status to "unknown" is actually the closest you would be able to get, but as you note this also returns inherited variation.

We would, however, be open to adding functionality to support this. We would not want to change the default behavior of inheritance-based searches for all users, but we would be happy to add a checkbox for "allow no calls" to the inheritance filter panel. Our team currently does not have the bandwidth to add new search functionality until later this year, so your options are

1. Wait until fall/ winter of this year for our team to add this support or
2. Have someone on your dev team add this support and put up a PR against the main seqr repo and our team will incorporate it. Our team would be happy to meet with your developers if they have any questions about this approach

Either way, we would appreciate you adding a "feature request" issue in github so we can track this request.

Best,
Hana Snow
Technical Lead, seqr