ClinVar

Description

Variant summary: FBN1 c.538+4A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict an impact on normal splicing: Three predict the variant weakens a 5' donor site. Two predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00033 in 246094 control chromosomes, predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 20-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.538+4A>G in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign.