NM_175914.5:c.1293C>T

CA9870529

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 687c2962-f779-42df-a5b2-589f15639a46

Approved on: 2023-01-12

Published on: 2023-01-12

HGVS expressions

NM_175914.5:c.1293C>T
NC_000020.11:g.44429599C>T
CM000682.2:g.44429599C>T
NC_000020.10:g.43058239C>T
CM000682.1:g.43058239C>T
NC_000020.9:g.42491653C>T
NG_009818.1:g.78799C>T
ENST00000316099.10:c.1359C>T
ENST00000316099.9:c.1359C>T
ENST00000316099.8:c.1359C>T
ENST00000316673.8:c.1293C>T
ENST00000372920.1:c.*1126C>T
ENST00000415691.2:c.1329C>T
ENST00000457232.5:c.1263C>T
ENST00000619550.4:c.1284C>T
NM_000457.4:c.1359C>T
NM_001030003.2:c.1263C>T
NM_001258355.1:c.1338C>T
NM_001287182.1:c.1254C>T
NM_001287183.1:c.1284C>T
NM_175914.4:c.1293C>T
NM_178849.2:c.1329C>T
NM_001030003.3:c.1263C>T
NM_001258355.2:c.1338C>T
NM_001287182.2:c.1254C>T
NM_178849.3:c.1329C>T
NM_000457.5:c.1359C>T
NM_000457.6:c.1359C>T
NM_001287183.2:c.1284C>T

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: BS1 BP4 BP7 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 1.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1293C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 431 (p.(Val431=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.754, which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00006015, which is greater than the MDEP threshold for BS1 (greater than 0.000033) (BS1). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; Internal lab contributor). In summary, c. 1293C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BS1, BP4, BP7, PP4.

Met criteria codes

• BS1: This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00006015, which is greater than or equal to the MDEP threshold for BS1 (greater than or equal to 0.000033).
• BP4: This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2).
• BP7: This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.754, which is below the MDEP cutoff of 2.0).
• PP4: This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (Internal lab contributor)