ClinVar Genomic variation as it relates to human health

The c.224+17dupT variant in the HNF4 homeobox A gene, HNF4A has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0008603, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor gain, suggesting that the variant has no impact on splicing (BP4). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and PP4 is not met (internal lab contributors). This variant was also identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.224+17dupT meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 11/16/2022): BA1, BP4, BP5.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Variant summary: HNF4A c.224+17dupT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.0019 in 245602 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 603.25 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF4A causing Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus phenotype (3.1e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.224+17dupT in individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.

Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs371937621 in MODY, yet.