Variant: NM_175914.5(HNF4A):c.640T>A (p.Ser214Thr)

CA16609462

397578 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: dd7583e7-e800-4b33-b44e-91c1d119e9c7

Approved on: 2024-05-09

Published on: 2024-05-09

HGVS expressions

NM_175914.5:c.640T>A
NM_175914.5(HNF4A):c.640T>A (p.Ser214Thr)
NC_000020.11:g.44418482T>A
CM000682.2:g.44418482T>A
NC_000020.10:g.43047122T>A
CM000682.1:g.43047122T>A
NC_000020.9:g.42480536T>A
NG_009818.1:g.67682T>A
ENST00000316673.9:c.640T>A
ENST00000316099.10:c.706T>A
ENST00000619550.5:c.680T>A
ENST00000683148.1:n.682T>A
ENST00000683657.1:n.1830T>A
ENST00000316099.9:c.706T>A
ENST00000316099.8:c.706T>A
ENST00000316673.8:c.640T>A
ENST00000372920.1:c.*473T>A
ENST00000415691.2:c.706T>A
ENST00000443598.6:c.706T>A
ENST00000457232.5:c.640T>A
ENST00000609795.5:c.640T>A
ENST00000619550.4:c.631T>A
NM_000457.4:c.706T>A
NM_001030003.2:c.640T>A
NM_001030004.2:c.640T>A
NM_001258355.1:c.685T>A
NM_001287182.1:c.631T>A
NM_001287183.1:c.631T>A
NM_001287184.1:c.631T>A
NM_175914.4:c.640T>A
NM_178849.2:c.706T>A
NM_178850.2:c.706T>A
NM_001030003.3:c.640T>A
NM_001030004.3:c.640T>A
NM_001258355.2:c.685T>A
NM_001287182.2:c.631T>A
NM_001287184.2:c.631T>A
NM_178849.3:c.706T>A
NM_178850.3:c.706T>A
NM_000457.5:c.706T>A
NM_000457.6:c.706T>A
NM_001287183.2:c.631T>A

Uncertain Significance

• Met criteria codes: PM1_Supporting PM2_Supporting PP3

• Not Met criteria codes: PM5

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.640T>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to threonine at codon 214 (p.Ser214Thr)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). A number of other missense variants at this codon (c.640T>G, p.Ser214Ala; c.641C>T, p.Ser214Phe; c.641C>A, p.Ser214Tyr) have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.640T>A 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): PP3, PM1_Supporting, PM2_Supporting.

Met criteria codes

• PM1_Supporting: This variant is located within the ligand-binding domain (codons 180-220) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

Not Met criteria codes

• PM5: A number of other missense variants at this codon (c.640T>G, p.Ser214Ala; c.641C>T, p.Ser214Phe; c.641C>A, p.Ser214Tyr) have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.