Variant: NM_175914.5(HNF4A):c.1199G>A (p.Arg400Gln)

Version: 1.1
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CA9870497

1411449 (ClinVar)

Gene: HNF4A (HGNC:3172)

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 33f51f86-e0ab-4a00-8188-2d14ba73a404

Approved on: 2025-06-09

Published on: 2025-06-09

HGVS expressions

NM_175914.5:c.1199G>A
NM_175914.5(HNF4A):c.1199G>A (p.Arg400Gln)
NC_000020.11:g.44428470G>A
CM000682.2:g.44428470G>A
NC_000020.10:g.43057110G>A
CM000682.1:g.43057110G>A
NC_000020.9:g.42490524G>A
NG_009818.1:g.77670G>A
ENST00000316673.9:c.1199G>A
ENST00000316099.10:c.1265G>A
ENST00000316099.9:c.1265G>A
ENST00000316099.8:c.1265G>A
ENST00000316673.8:c.1199G>A
ENST00000372920.1:c.*1032G>A
ENST00000415691.2:c.1252+13G>A
ENST00000457232.5:c.1186+13G>A
ENST00000619550.4:c.1190G>A
NM_000457.4:c.1265G>A
NM_001030003.2:c.1186+13G>A
NM_001258355.1:c.1244G>A
NM_001287182.1:c.1177+13G>A
NM_001287183.1:c.1190G>A
NM_175914.4:c.1199G>A
NM_178849.2:c.1252+13G>A
NM_001030003.3:c.1186+13G>A
NM_001258355.2:c.1244G>A
NM_001287182.2:c.1177+13G>A
NM_178849.3:c.1252+13G>A
NM_000457.5:c.1265G>A
NM_000457.6:c.1265G>A
NM_001287183.2:c.1190G>A

Likely Benign

• Met criteria codes: BS1 BP4 BP5

• Not Met criteria codes: PS4 PP4

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.1199G>A variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 400 (p.(Arg400Gln)) of NM_175914.5. This variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009487, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in at least 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar Variation ID: 1411449, internal lab contributors). Several of these individuals have antibody-negative diabetes; however, the calculated MODY probability is <50% (internal lab contributors). Additionally, this variant is predicted to be benign by computational evidence, with a REVEL score of 0.06199, which is less than the MDEP threshold of 0.15 (BP4). Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributor). In summary, this variant meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BS1, BP4, BP5.

Met criteria codes

• BS1: This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009487, which is greater the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1).
• BP4: This variant is predicted to be benign by computational evidence, with a REVEL score of 0.06199, which is less than the MDEP threshold of 0.15 (BP4).
• BP5: This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributor).

Not Met criteria codes

• PS4: This variant was identified in at least 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar Variation ID: 1411449, internal lab contributors).
• PP4: This variant was identified in multiple individuals with antibody-negative diabetes; however, the calculated MODY probability is <50% (internal lab contributors).