Variant: NM_175914.5(HNF4A):c.1127T>G (p.Met376Arg)

CA409110090

1679313 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 9b863ac0-29ea-4eb1-954a-1155003a8a91

Approved on: 2025-01-03

Published on: 2025-01-03

HGVS expressions

NM_175914.5:c.1127T>G
NM_175914.5(HNF4A):c.1127T>G (p.Met376Arg)
NC_000020.11:g.44428398T>G
CM000682.2:g.44428398T>G
NC_000020.10:g.43057038T>G
CM000682.1:g.43057038T>G
NC_000020.9:g.42490452T>G
NG_009818.1:g.77598T>G
ENST00000316673.9:c.1127T>G
ENST00000316099.10:c.1193T>G
ENST00000316099.9:c.1193T>G
ENST00000316099.8:c.1193T>G
ENST00000316673.8:c.1127T>G
ENST00000372920.1:c.*960T>G
ENST00000415691.2:c.1193T>G
ENST00000457232.5:c.1127T>G
ENST00000619550.4:c.1118T>G
NM_000457.4:c.1193T>G
NM_001030003.2:c.1127T>G
NM_001258355.1:c.1172T>G
NM_001287182.1:c.1118T>G
NM_001287183.1:c.1118T>G
NM_175914.4:c.1127T>G
NM_178849.2:c.1193T>G
NM_001030003.3:c.1127T>G
NM_001258355.2:c.1172T>G
NM_001287182.2:c.1118T>G
NM_178849.3:c.1193T>G
NM_000457.5:c.1193T>G
NM_000457.6:c.1193T>G
NM_001287183.2:c.1118T>G

Uncertain Significance

• Met criteria codes: PP4_Moderate PM2_Supporting

• Not Met criteria codes: PM1 BP4 PP3

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

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1127T>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of methionine to arginine at codon 376 (p.(Met376Arg)) of NM_175914.5. This variant has a REVEL score of 0.235, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.1127T>G 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): PP4_Moderate, PM2_Supporting.

Met criteria codes

• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 1 copy in gnomAD 4.0 (Grpmax FAF = 0)

Not Met criteria codes

• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: This variant has a REVEL score of 0.235, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function.
• PP3: This variant has a REVEL score of 0.235, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function.