NM_175914.5:c.124G>A

CA9870171

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 777b2b75-0616-4c42-89cc-a574cf54cce6

Approved on: 2024-04-06

Published on: 2024-04-06

HGVS expressions

NM_175914.5:c.124G>A
NC_000020.11:g.44406132G>A
CM000682.2:g.44406132G>A
NC_000020.10:g.43034772G>A
CM000682.1:g.43034772G>A
NC_000020.9:g.42468186G>A
NG_009818.1:g.55332G>A
ENST00000316673.9:c.124G>A
ENST00000316099.10:c.190G>A
ENST00000619550.5:c.164G>A
ENST00000681977.1:c.166G>A
ENST00000682169.1:c.143G>A
ENST00000683148.1:n.166G>A
ENST00000683657.1:n.166G>A
ENST00000684046.1:c.166G>A
ENST00000684136.1:c.166G>A
ENST00000684476.1:c.147G>A
ENST00000316099.9:c.190G>A
ENST00000316099.8:c.190G>A
ENST00000316673.8:c.124G>A
ENST00000372920.1:c.281G>A
ENST00000415691.2:c.190G>A
ENST00000443598.6:c.190G>A
ENST00000457232.5:c.124G>A
ENST00000609262.5:c.115G>A
ENST00000609795.5:c.124G>A
ENST00000619550.4:c.115G>A
NM_000457.4:c.190G>A
NM_001030003.2:c.124G>A
NM_001030004.2:c.124G>A
NM_001258355.1:c.169G>A
NM_001287182.1:c.115G>A
NM_001287183.1:c.115G>A
NM_001287184.1:c.115G>A
NM_175914.4:c.124G>A
NM_178849.2:c.190G>A
NM_178850.2:c.190G>A
NM_001030003.3:c.124G>A
NM_001030004.3:c.124G>A
NM_001258355.2:c.169G>A
NM_001287182.2:c.115G>A
NM_001287184.2:c.115G>A
NM_178849.3:c.190G>A
NM_178850.3:c.190G>A
NM_000457.5:c.190G>A
NM_000457.6:c.190G>A
NM_001287183.2:c.115G>A

Likely Pathogenic

• Met criteria codes: PS4 PP1 PP3 PM2_Supporting PM1_Supporting

• Not Met criteria codes: 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.124G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to arginine at codon 42 (p.(Gly42Arg)) of NM_175914.5. This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as crucial for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 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 Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 26552609, internal lab contributors). However, the MODY probability is either unable to be calculated due to lack of clinical information or the calculated MODY probability is <50% (PMID:26552609, internal lab contributors). This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID:26552609). In summary, c.124G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PP1, PP3, PM1_Supporting, PM2_Supporting.

Met criteria codes

• PS4: This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 26552609, internal lab contributors).
• PP1: This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID:26552609).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PM2_Supporting: This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 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 Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting).
• PM1_Supporting: This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as crucial for the protein's function by the ClinGen MDEP (PM1_Supporting).

Not Met criteria codes

• PP4: This variant was identified in multiple individuals with diabetes, however the MODY probability is either unable to be calculated due to lack of clinical information or the calculated MODY probability is <50% (PMID:26552609, internal lab contributors).