Variant: NM_175914.5(HNF4A):c.724G>A (p.Val242Met)

CA9870370

917409 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: b49af763-d6c1-4a0c-98dd-a82bbb57b0ce

Approved on: 2024-09-18

Published on: 2024-09-18

HGVS expressions

NM_175914.5:c.724G>A
NM_175914.5(HNF4A):c.724G>A (p.Val242Met)
NC_000020.11:g.44419774G>A
CM000682.2:g.44419774G>A
NC_000020.10:g.43048414G>A
CM000682.1:g.43048414G>A
NC_000020.9:g.42481828G>A
NG_009818.1:g.68974G>A
ENST00000316673.9:c.724G>A
ENST00000316099.10:c.790G>A
ENST00000619550.5:c.764G>A
ENST00000683148.1:n.766G>A
ENST00000683657.1:n.1914G>A
ENST00000316099.9:c.790G>A
ENST00000316099.8:c.790G>A
ENST00000316673.8:c.724G>A
ENST00000372920.1:c.*557G>A
ENST00000415691.2:c.790G>A
ENST00000443598.6:c.790G>A
ENST00000457232.5:c.724G>A
ENST00000609795.5:c.724G>A
ENST00000619550.4:c.715G>A
NM_000457.4:c.790G>A
NM_001030003.2:c.724G>A
NM_001030004.2:c.724G>A
NM_001258355.1:c.769G>A
NM_001287182.1:c.715G>A
NM_001287183.1:c.715G>A
NM_001287184.1:c.715G>A
NM_175914.4:c.724G>A
NM_178849.2:c.790G>A
NM_178850.2:c.790G>A
NM_001030003.3:c.724G>A
NM_001030004.3:c.724G>A
NM_001258355.2:c.769G>A
NM_001287182.2:c.715G>A
NM_001287184.2:c.715G>A
NM_178849.3:c.790G>A
NM_178850.3:c.790G>A
NM_000457.5:c.790G>A
NM_000457.6:c.790G>A
NM_001287183.2:c.715G>A

Benign

• Met criteria codes: BS3_Supporting BA1 PP3

• Not Met criteria codes: PS3 PP4 PM1

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.724G>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of valine to methionine at codon 242(p.(Val242Met)) of NM_175914.5. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0003423, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.81, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies performed on this variant showed transactivation activity >= 75% of that of wildtype, providing evidence that the variant does not affect HNF4A function (BS3_Supporting; PMIDs: 15728204, 10666040, 10389854). In summary, c.724G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BA1, PP3, BS3_Supporting.

Met criteria codes

• BS3_Supporting: Functional studies performed on this variants are consistent with transactivation activity >= 75% of that of wildtype(BS3_Supporting; PMIDs: 15728204, 10666040, 10389854).
• BA1: This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0003423, which is greater than the MDEP threshold for BA1 (0.0001) (BA1).
• PP3: This variant is predicted to be deleterious by computational evidence with a REVEL score of 0.81, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

Not Met criteria codes

• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50% (internal contributor).
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline