Fig. 6

Scaling down the PVS1 criteria of canonical splice site variants in KMT2D. Left: another a priori PVS1 variant NM_003482.4(KMT2D):c.5189-1G > C, present in 11 individuals in UK Biobank. This variant is predicted to result in an in-frame rescuing acceptor site, deleting 8 poorly conserved amino acids. Right: SpliceAI-visual outputs and BAM from one heterozygous from gnomAD of NM_003482.4(KMT2D):c.5782 + 1G > A. This variant is present in 3 individuals in gnomAD, which is not consistent with the penetrance of loss-of-function variants of KMT2D. Also, the mild rescuing DS of 0.28 is added to a nonzero RS on the reference allele (delta score pitfall) and is predicted to result in a complete rescue of this donor site, with the in-frame retention of 9 bp