Dear Team,
The number of expected and observed pLoF variants for CYP8B1 seems unusual. We actually observed 74 pLoF variants in the GnomAD database, correct?
We may observe 74 pLoF variants in the database across all transcripts and variant types in this gene, but the constraint table only displays pLoF variants that meet the following criteria:
- single nucleotide variants
- in the MANE Select transcript
- with MAF < 0.1%
- that are considered high confidence by LOFTEE
- in the exome sequenced samples
For this particular gene, if you go to the page for the MANE select transcript (gnomAD), you will see 66 pLoF variants listed. Of those, only 5 are considered “high confidence” (as noted by the lack of the LC pLoF flag) and only two are single nucleotide variants.
One faster way to find this is to uncheck “Genomes” and “indels” and then sort by the “Flags” column:
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Thank you, Kaitlin, for the thorough explanation. It was very helpful and much appreciated. @Kaitlin_Samocha
Hi Kaitlin, I am wondering why we have in the exome sequenced samples this requirement?
Thanks.
Shicheng
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@Shicheng_Guo We computed constraint only on exomes for historical reasons, since we had much larger sample size in v2 exomes, as Julia mentioned in this reply: the v4 constraint metrics are still experimental, we are looking into incorporating genomes once we have enough power. Please stay tuned for future gnomAD releases.