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]

Variant: NM_175914.5(HNF4A):c.844G>A (p.Asp282Asn)

Curation Version - 1.0
Curation History
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CA9870393

393444 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 855c690e-c9aa-45d4-bde7-82ce02a860ed

Approved on: 2024-09-26

Published on: 2024-09-26

HGVS expressions

NM_175914.5:c.844G>A

NM_175914.5(HNF4A):c.844G>A (p.Asp282Asn)

NC_000020.11:g.44424035G>A

CM000682.2:g.44424035G>A

NC_000020.10:g.43052675G>A

CM000682.1:g.43052675G>A

NC_000020.9:g.42486089G>A

NG_009818.1:g.73235G>A

ENST00000316673.9:c.844G>A

ENST00000316099.10:c.910G>A

ENST00000619550.5:c.884G>A

ENST00000316099.9:c.910G>A

ENST00000316099.8:c.910G>A

ENST00000316673.8:c.844G>A

ENST00000372920.1:c.*677G>A

ENST00000415691.2:c.910G>A

ENST00000443598.6:c.910G>A

ENST00000457232.5:c.844G>A

ENST00000609795.5:c.844G>A

ENST00000619550.4:c.835G>A

NM_000457.4:c.910G>A

NM_001030003.2:c.844G>A

NM_001030004.2:c.844G>A

NM_001258355.1:c.889G>A

NM_001287182.1:c.835G>A

NM_001287183.1:c.835G>A

NM_001287184.1:c.835G>A

NM_175914.4:c.844G>A

NM_178849.2:c.910G>A

NM_178850.2:c.910G>A

NM_001030003.3:c.844G>A

NM_001030004.3:c.844G>A

NM_001258355.2:c.889G>A

NM_001287182.2:c.835G>A

NM_001287184.2:c.835G>A

NM_178849.3:c.910G>A

NM_178850.3:c.910G>A

NM_000457.5:c.910G>A

NM_000457.6:c.910G>A

NM_001287183.2:c.835G>A

Uncertain Significance

PP4 PP3 PM2

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.844G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of aspartate to asparagine at codon 282 (p.(Asp282Asn)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax minor filtering allele frequency of 0.000003000 (equal to the MDEP threshold of 0.000003), however, it has 3 copies in the European non-Finnish population (over the MDEP threshold of 2); therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant has a REVEL score of 0.42, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (PMID: 27913849). In summary, c.844G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): no criteria met.

PP4

This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (PMID: 27913849).

PP3

This variant has a REVEL score of 0.42, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function.

PM2

This variant has a gnomAD v2.1.1 Grpmax minor filtering allele frequency of 0.000003000 (equal to the MDEP threshold of 0.000003), however, it has 3 copies in the European non-Finnish population (over the MDEP threshold of 2); therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. Gnomad v4.1 grpmax: 0.000007390 - also does not meet the ClinGen MDEP-established cutoff for PM2_Supporting.

Curation History

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