ClinVar

Description

Variant summary: NCF4 c.172C>T (p.Arg58Cys) results in a non-conservative amino acid change located in the phox homology domain (IPR001683) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251398 control chromosomes (gnomAD), predominantly at a frequency of 0.0095 within the Latino subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 38-fold of the estimated maximal expected allele frequency for a pathogenic variant in NCF4 causing Chronic Granulomatous Disease (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge no penetrant association of c.172C>T has been reported in individuals affected with Chronic Granulomatous Disease; 5 homozygous individuals of Latino origin were reported by van de Geer_2018, two unrelated individuals that appeared to have a mild phenotype resembling atypical Granulomatous disease, and three unaffected siblings. At least one study evaluated the impact of the variant on protein function, but found little evidence of functional impairment (van de Geer_2018). Four assessments for this variant have been submitted to ClinVar after 2014. Three submitters classified the variant as benign/likely benign and one classified it as VUS. Based on the evidence outlined above, the variant was classified as benign.