rs147638455
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. BS4BP5PP4_ModerateBS3_SupportingBA1
This summary comes from the ClinGen Evidence Repository: The c.1321A>G p.(Ile441Val) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005025, which is greater than the MDEP threshold for BA1 (BA1). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and GAD negative) (PP4_Moderate, internal contributors). There is evidence in vitro that this variant has identical transactivation activity to wildtype, indicating that this variant does not impact protein function (BS3_Supporting, PMID:30191603). This variant does not segregate with diabetes in three families (BS4; internal lab contributors, PMIDs: 25905084, 10227563, 33324081). This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1321A>G p.(Ile441Val) meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): BA1, PP4_Moderate, BS3_Supporting, BS4, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213913/MONDO:0015967/085
Frequency
Consequence
NM_175914.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000639 AC: 97AN: 151798Hom.: 3 Cov.: 31
GnomAD3 exomes AF: 0.000370 AC: 93AN: 251452Hom.: 0 AF XY: 0.000397 AC XY: 54AN XY: 135914
GnomAD4 exome AF: 0.000268 AC: 392AN: 1461886Hom.: 5 Cov.: 32 AF XY: 0.000298 AC XY: 217AN XY: 727246
GnomAD4 genome AF: 0.000639 AC: 97AN: 151918Hom.: 3 Cov.: 31 AF XY: 0.000768 AC XY: 57AN XY: 74240
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:3
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 441 of the HNF4A protein (p.Ile441Val). This variant is present in population databases (rs147638455, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 10227563, 21105491, 23247789, 26059258, 31595705, 33846082, 34373539, 35256061). This variant is also known as p.Ile454Val, p.Ile463Val. ClinVar contains an entry for this variant (Variation ID: 36345). 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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This variant is associated with the following publications: (PMID: 23227446, 27884173, 24097065, 25905084, 26059258, 10227563, 21105491, 10768098, 31264968, 31595705) -
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HNF4A: BS1 -
not specified Benign:2
Variant summary: HNF4A c.1321A>G (p.Ile441Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251452 control chromosomes, predominantly at a frequency of 0.00072 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 230 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 a benign polymorphism found primarily in populations of Latino origin. c.1321A>G has been reported in the literature (example: deSantana_2019, Majidi_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes of the Young 1/Neonatal Diabetes Mellitus. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Guo_2019). Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=1) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
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Familial hyperinsulinism Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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
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Autosomal dominant polycystic liver disease Uncertain:1
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Maturity-onset diabetes of the young type 1 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Maturity onset diabetes mellitus in young Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Monogenic diabetes Benign:1
The c.1321A>G p.(Ile441Val) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005025, which is greater than the MDEP threshold for BA1 (BA1). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and GAD negative) (PP4_Moderate, internal contributors). There is evidence in vitro that this variant has identical transactivation activity to wildtype, indicating that this variant does not impact protein function (BS3_Supporting, PMID: 30191603). This variant does not segregate with diabetes in three families (BS4; internal lab contributors, PMIDs: 25905084, 10227563, 33324081). This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1321A>G p.(Ile441Val) meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): BA1, PP4_Moderate, BS3_Supporting, BS4, BP5. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at