ClinVar

Description

Variant summary: MPO c.2031-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing , and the predominant products were truncated MPO (Haskamp_2020), such mRNA products are not subject to NMD. The variant allele was found at a frequency of 0.0044 in 251174 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD v2), and in gnomAD v4 dataset, this vairant was found a frequency of 0.0066 in 1179978 control chromosomes in European (non-Finnish) group with 25 homozygotes, suggesting that the variant may be benign. c.2031-2A>C has been reported in the literature in at-least three individuals affected with Myeloperoxidase Deficiency (example, Marchetti_2004). Additionally, no pathogenic missense or in-frame changes from the last exon have been reported in ClinVar, suggesting the disrupted last exon may not be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 32758447, 15108282). ClinVar contains an entry for this variant (Variation ID: 3632). Based on the evidence outlined above, the variant was classified as uncertain significance.