rs1063239
Variant summary
Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4
This summary comes from the ClinGen Evidence Repository: The c.1267C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of proline to serine at codon 423 (p.(Pro423Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003), however, it has > 2 copies observed in the European non-Finnish population and other subpopulations; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant is predicted to be benign by computational evidence, with a REVEL score of 0.059, which is less than or equal to the MDEP threshold of 0.15 (BP4). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID:22308320). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID:15111529 ). In summary, c.1267C>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA231163/MONDO:0015967/085
Frequency
Consequence
NM_175914.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251382Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135872
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727232
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74266
ClinVar
Submissions by phenotype
not provided Uncertain:2
- -
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 423 of the HNF4A protein (p.Pro423Ser). This variant is present in population databases (rs1063239, gnomAD 0.02%). This missense change has been observed in individual(s) with HNF4A-related conditions (PMID: 15111529). This variant is also known as Pro436Ser or Pro445Ser . ClinVar contains an entry for this variant (Variation ID: 129237). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects HNF4A function (PMID: 22308320). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
Variant summary: HNF4A c.1267C>T (p.Pro423Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1267C>T has been reported in the literature in individuals affected with Diabetes (example, Aguilera_2004) and as "not possibly/putatively pathogenic" at-least one case in the Jackson Heart Study cohort, in which a majority (>80%) of variant carriers did not develop diabetes. These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus. To our knowledge, no informative experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15111529, 22308320, 24097065, 30648609). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Type 2 diabetes mellitus;C1852093:Maturity-onset diabetes of the young type 1;C4014962:Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young Uncertain:1
- -
Monogenic diabetes Uncertain:1
The c.1267C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of proline to serine at codon 423 (p.(Pro423Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003), however, it has > 2 copies observed in the European non-Finnish population and other subpopulations; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant is predicted to be benign by computational evidence, with a REVEL score of 0.059, which is less than or equal to the MDEP threshold of 0.15 (BP4). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 22308320). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 15111529 ). In summary, c.1267C>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): BP4. -
Maturity onset diabetes mellitus in young Uncertain:1
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 rs1063239 in MODY, yet. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at