Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_175914.5(HNF4A):c.1017C>T (p.Phe339=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA9870428

586010 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d06bf543-9b05-47e7-b2e4-01cd44d167cc

Approved on: 2023-01-12

Published on: 2023-01-12

HGVS expressions

NM_175914.5:c.1017C>T

NM_175914.5(HNF4A):c.1017C>T (p.Phe339=)

NC_000020.11:g.44424208C>T

CM000682.2:g.44424208C>T

NC_000020.10:g.43052848C>T

CM000682.1:g.43052848C>T

NC_000020.9:g.42486262C>T

NG_009818.1:g.73408C>T

ENST00000316099.10:c.1083C>T

ENST00000619550.5:n.1057C>T

ENST00000316099.9:c.1083C>T

ENST00000316099.8:c.1083C>T

ENST00000316673.8:c.1017C>T

ENST00000372920.1:c.*850C>T

ENST00000415691.2:c.1083C>T

ENST00000443598.6:c.1083C>T

ENST00000457232.5:c.1017C>T

ENST00000609795.5:c.1017C>T

ENST00000619550.4:c.1008C>T

NM_000457.4:c.1083C>T

NM_001030003.2:c.1017C>T

NM_001030004.2:c.1017C>T

NM_001258355.1:c.1062C>T

NM_001287182.1:c.1008C>T

NM_001287183.1:c.1008C>T

NM_001287184.1:c.1008C>T

NM_175914.4:c.1017C>T

NM_178849.2:c.1083C>T

NM_178850.2:c.1083C>T

NM_001030003.3:c.1017C>T

NM_001030004.3:c.1017C>T

NM_001258355.2:c.1062C>T

NM_001287182.2:c.1008C>T

NM_001287184.2:c.1008C>T

NM_178849.3:c.1083C>T

NM_178850.3:c.1083C>T

NM_000457.5:c.1083C>T

NM_000457.6:c.1083C>T

NM_001287183.2:c.1008C>T

Likely Benign

BS2 BP7 BP4

PM2 BS1

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1017C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 339 (p.(Phe339=)) 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 -3.055, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c. 1017C>T variant in gnomAD v2.1.1 is 0.00002141, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (PMID: 29026101)(MDEP internal contributor; BS2). In summary, c. 1017C>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 1.0.0, approved 11/16/22): BS2, BP4, BP7.

BS2

This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (PMID: 29026101). (MDEP internal contributor)

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 -3.055, which is below the MDEP cutoff of 2.0)

BP4

This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2)

PM2

The Popmax frequency of the c. 1017C>T variant in gnomAD v2.1.1 is 0.00002141, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

BS1

Curation History

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