rs202105574
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BS2_Supporting
The NM_175914.5(HNF4A):c.658G>A(p.Val220Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain risk allele (★★).
Frequency
Consequence
NM_175914.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 249892Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135192
GnomAD4 exome AF: 0.00000959 AC: 14AN: 1460308Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726536
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152312Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74472
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 220 of the HNF4A protein (p.Val220Met). This variant is present in population databases (rs202105574, gnomAD 0.005%). This missense change has been observed in individual(s) with HNF4A-related conditions (PMID: 26552609, 30586318, 31291970). This variant is also known as c.724G>A (p.Val242Met). ClinVar contains an entry for this variant (Variation ID: 562363). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. 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. -
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Maturity onset diabetes mellitus in young Other: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 rs202105574 in MODY, yet. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at