Update LoF curations #1798
Update LoF curations #1798
Conversation
rileyhgrant
force-pushed
the
lof-curations-update
branch
3 times, most recently
from
3ab5e0a to
4fc74bb
Compare
graphql-api/src/queries/variant-datasets/gnomad-v4-variant-queries.ts
Outdated
Show resolved
Hide resolved
rileyhgrant
force-pushed
the
lof-curations-update
branch
3 times, most recently
from
87866c5 to
987fba7
Compare
There was a problem hiding this comment.
thank you for adding these! I have a few questions about the documentation.
since new LoF curation results are being loaded for v4, should we update this page as well? I think we should also release a quick changelog entry announcing this update
| For likely not LoF and not LoF variants, this curation supports the conclusion that either these variants are likely the result of a technical sequencing error, or their predicted effect based on our extensive manual curation is not LoF. For those variants with technical errors that are also deemed not LoF, the allele frequency of these variants in gnomAD should not be considered the true frequency of these variants in gnomAD. For other variants that have been curated as likely not LoF and not LoF, these may still be pathogenic variants, but the predicted mechanism for these variants in causing disease is not predicted to be due to LoF. For example, a nonsense variant in the last exon would not be expected to result in nonsense mediated decay but it could still disrupt the function of the protein if the terminal end of the protein was essential for function. In addition, a variant that is located in a homopolymer repeat could be an artifact of sequencing in gnomAD, but if it is identified in an individual with disease (where it was likely Sanger confirmed), then the mechanism is actually likely to be LoF. | ||
|
|
||
| Uncertain LoF variants represent cases where we were unable to reach a more conclusive classification and therefore should not be interpreted as falling into either of the above two categories. | ||
| For _likely not LoF_ and _not LoF_ variants, this curation supports the conclusion that either these variants are likely the result of a technical sequencing error, or their predicted effect based on our extensive manual curation is to escape NMD. For those variants with technical errors that are also classified as _not LoF_, the allele frequency of these variants in gnomAD should not be considered the true frequency of these variants. For other variants that have been curated as _likely not LoF_ and _not LoF_, these may still be pathogenic variants, but they are expected to escape NMD. |
There was a problem hiding this comment.
did the curation team mention why they no longer want to include the additional context here (e.g., "For example, a nonsense variant in the last exon would not be expected to result in nonsense mediated decay but it could still disrupt the function of the protein if the terminal end of the protein was essential for function.")?
There was a problem hiding this comment.
Ah, they did not, I just yoinked the new text from a google doc. I'll double check on this one, and use the changes you suggested for all the others.
Good call, we'll remove the lof curations row from that table. I'll double check on the removal of detail in that one flag, edit the other flags per your suggestions, add a link to that paper in the v4 downloads section, and prep a brief changelog. Thank you for the review KC! |
rileyhgrant
force-pushed
the
lof-curations-update
branch
2 times, most recently
from
a25a198 to
fcdf4d1
Compare
rileyhgrant
force-pushed
the
lof-curations-update
branch
from
fcdf4d1 to
c695e05
Compare
Related changelog PR: broadinstitute/gnomad-blog#195