Update Post “2026-03-gnomad-v4-1-1”

Author: ch-kr

content/posts/2026-03-gnomad-v4-1-1.md

@@ -42,7 +42,13 @@ As part of the gnomAD v4.1.1 minor release, we have now included constraint metr
 
 ![Screenshot of variant 13-32398763-ATATC-A Ensembl VEP consequences in gnomAD v4](../images/v4_hc_plof_2.png)
 
-Users also reported variants being inappropriately flagged in v4. For example, this variant is flagged as low confidence in [v4](https://gnomad.broadinstitute.org/variant/11-65780304-CT-C?dataset=gnomad_r4) but is high confidence in [v2](https://gnomad.broadinstitute.org/gene/ENSG00000254470?dataset=gnomad_r2_1):  
+Users also reported variants being inappropriately flagged in v4. For example, this variant is flagged as low confidence in [v4](https://gnomad.broadinstitute.org/variant/11-65780304-CT-C?dataset=gnomad_r4) but is high confidence in [v2](https://gnomad.broadinstitute.org/gene/ENSG00000254470?dataset=gnomad_r2_1):
+
+![Screenshot of variant 11-65780304-CT-C in gnomAD v4](../images/v4_lc_plof.png)
+
+  
+
+![Screenshot of variant 11-65547775-CT-C in gnomAD v2](../images/v2_hc_plof.png)
 
 To address this issue, we have updated the GERP distance threshold to 0.0 and re-annotated LOFTEE in gnomAD v4.1.1. GERP distances measure evolutionary constraint, with positive values indicating conservation and negative values indicating less constraint. Terminal truncations towards the ends of transcripts do not have large negative GERP distance values, as they are not deleting a large number of bases, which meant they were not correctly being flagged with the previous threshold value (-58.0). Changing the GERP distance threshold to 0.0 updates the behavior of this flag to indicate that terminal truncations with negative GERP scores (i.e., variants that delete less evolutionarily constrained bases) are low-confidence pLoFs.