ClinVar

Description

Variant summary: The CFTR c.3874-103delT variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESE Finder predicts no significant change in ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. The variant of interest was observed in the large, broad control population that contains ExAC data and additional whole genome sequences, gnomAD, with an allele frequency of 3/30902, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0062697). However, this observation in gnomAD needs to be cautiously considered due to the site being indicated as a "low-quality site," in addition, the LCA VSG has yet to validate this database as of yet. To our knowledge, the variant of interest has not been reported in affected individuals via publications or clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. A reputable database does cite the variant and indicates that the variant is a "he presumed polymorphism was detected by SSCP/heteroduplex analysis and characterised by direct sequencing. It has not been observed previously on over 100 non-[delta]F508 CF chromosomes. 4006-103delT was observed in a normal adult female undergoing screening due to infertility treatment for her partner who was a [delta]F508 carrier and who had CBAVD. This change is highly likely to be a polymorphism." Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.