In silico pathogenicity evaluation of QDPR: c.۱۳۵T>A (p.Asn۴۵Lys) variant

Genetic mutations occurred in the genes related to BH۴ cofactor, including quinoid dihydropteridinereductase (QDPR), may lead to hyperphenylalaninemia (HPA). DHPR deficiency is caused by defects in thecorresponding gene QDPR (۱). In this study, we evaluated the pathogenicity of QDPR: c.۱۳۵T>A(p.Asn۴۵Lys) variant using ten in silico predictive tools including PANTHER PSEP, PhD-SNPg,PROVEAN, Mutation Taster, SNPs & GO, FATHMM-XF, I-Mutant Disease, PolyPhen-۲, CADD, andSIFT. NM_۰۰۰۳۲۰.۳ and P۰۹۴۱۷-۱ were used as reference sequences. Except for PhD- SNPg, FATHMMXF,and SNPs & GO, the other seven in silico tools predicted deleterious effects for this variant. QDPR:c.۱۳۵T>A (p.Asn۴۵Lys) variant had been reported recently for the first time in an Iranian patient with DHPRdeficiency (in compound heterozygous form) (۲). There were no reports of this variant in the literature aswell as in the LOVD, HGMD, dbSNP, ClinVar, gnomAD, ۱KGP, and BIOPKU public databases. Inconclusion, with a threshold of deleterious effects in seven or more in silico predictive tools, QDPR:c.۱۳۵T>A (p.Asn۴۵Lys) variant could be accepted as a pathogenic variant. However, for its finalclassification, it is necessary to consider the other criteria provided by American College of Medical Geneticsand Genomics (ACMG-AMP) guidelines (۳).