Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_175914.5(HNF4A):c.427A>G (p.Ile143Val)

CA9870271

586016 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0a920e21-eaa7-4ca3-889a-b29fba2c365b

Approved on: 2024-05-09

Published on: 2024-05-09

HGVS expressions

NM_175914.5:c.427A>G

NM_175914.5(HNF4A):c.427A>G (p.Ile143Val)

NC_000020.11:g.44414507A>G

CM000682.2:g.44414507A>G

NC_000020.10:g.43043147A>G

CM000682.1:g.43043147A>G

NC_000020.9:g.42476561A>G

NG_009818.1:g.63707A>G

ENST00000316673.9:c.427A>G

ENST00000316099.10:c.493A>G

ENST00000619550.5:c.467A>G

ENST00000683148.1:n.469A>G

ENST00000683657.1:n.1617A>G

ENST00000316099.9:c.493A>G

ENST00000316099.8:c.493A>G

ENST00000316673.8:c.427A>G

ENST00000372920.1:c.*260A>G

ENST00000415691.2:c.493A>G

ENST00000443598.6:c.493A>G

ENST00000457232.5:c.427A>G

ENST00000609795.5:c.427A>G

ENST00000619550.4:c.418A>G

NM_000457.4:c.493A>G

NM_001030003.2:c.427A>G

NM_001030004.2:c.427A>G

NM_001258355.1:c.472A>G

NM_001287182.1:c.418A>G

NM_001287183.1:c.418A>G

NM_001287184.1:c.418A>G

NM_175914.4:c.427A>G

NM_178849.2:c.493A>G

NM_178850.2:c.493A>G

NM_001030003.3:c.427A>G

NM_001030004.3:c.427A>G

NM_001258355.2:c.472A>G

NM_001287182.2:c.418A>G

NM_001287184.2:c.418A>G

NM_178849.3:c.493A>G

NM_178850.3:c.493A>G

NM_000457.5:c.493A>G

NM_000457.6:c.493A>G

NM_001287183.2:c.418A>G

Uncertain Significance

PM2_Supporting

PP3 PM1

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.427A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNFA, causes an amino acid change of isoleucine to valine at codon 143 (p.(Ile143Val)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and zero copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant has a REVEL score of 0.445, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, the c.427A>G variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting.

PM2_Supporting

This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and zero copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting).

PP3

This variant has a REVEL score of 0.445, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function.

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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