Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification.

PURPOSE: We evaluated the Exome Aggregation Consortium (ExAC) database as a control cohort to classify variants across a diverse set of genes spanning dominant and recessively inherited disorders. METHODS: The frequency of pathogenic variants in ExAC was compared with the estimated maximal pathogenic allele frequency (MPAF), based on the disease prevalence, penetrance, inheritance, allelic and locus heterogeneity of each gene. Additionally, the observed carrier frequency and the ethnicity-specific variant distribution were compared between ExAC and the published literature. RESULTS: The carrier frequency and ethnic distribution of pathogenic variants in ExAC were concordant with reported estimates. Of 871 pathogenic/likely pathogenic variants across 19 genes, only 3 exceeded the estimated MPAF. Eighty-four percent of variants with ExAC frequencies above the estimated MPAF were classified as "benign." Additionally, 20% of the cardiac and 19% of the Lynch syndrome gene variants originally classified as "VUS" occurred with ExAC frequencies above the estimated MPAF, making these suitable for reassessment. CONCLUSIONS: The ExAC database is a useful source for variant classification and is not overrepresented for pathogenic variants in the genes evaluated. However, the mutational spectrum, pseudogenes, genetic heterogeneity, and paucity of literature should be considered in deriving meaningful classifications using ExAC.Genet Med 18 8, 850-854.

Identification and characterization of Drosophila Snurportin reveals a role for the import receptor Moleskin/importin-7 in snRNP biogenesis.

Nuclear import is an essential step in small nuclear ribonucleoprotein (snRNP) biogenesis. Snurportin1 (SPN1), the import adaptor, binds to trimethylguanosine (TMG) caps on spliceosomal small nuclear RNAs. Previous studies indicated that vertebrate snRNP import requires importin-ß, the transport receptor that binds directly to SPN1. We identify CG42303/snup as the Drosophila orthologue of human snurportin1 (SNUPN). Of interest, the importin-ß binding (IBB) domain of SPN1, which is essential for TMG cap-mediated snRNP import in humans, is not well conserved in flies. Consistent with its lack of an IBB domain, we find that Drosophila SNUP (dSNUP) does not interact with Ketel/importin-ß. Fruit fly snRNPs also fail to bind Ketel; however, the importin-7 orthologue Moleskin (Msk) physically associates with both dSNUP and spliceosomal snRNPs and localizes to nuclear Cajal bodies. Strikingly, we find that msk-null mutants are depleted of the snRNP assembly factor, survival motor neuron, and the Cajal body marker, coilin. Consistent with a loss of snRNP import function, long-lived msk larvae show an accumulation of TMG cap signal in the cytoplasm. These data indicate that Ketel/importin-ß does not play a significant role in Drosophila snRNP import and demonstrate a crucial function for Msk in snRNP biogenesis.