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

Variant: NM_175914.5(HNF4A):c.321C>T (p.Ala107=)

CA9870224

338426 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f50fb228-dc1c-42f2-8185-4f3a9600a217

HGVS expressions

NM_175914.5:c.321C>T
NM_175914.5(HNF4A):c.321C>T (p.Ala107=)
NC_000020.11:g.44413695C>T
CM000682.2:g.44413695C>T
NC_000020.10:g.43042335C>T
CM000682.1:g.43042335C>T
NC_000020.9:g.42475749C>T
NG_009818.1:g.62895C>T
ENST00000316099.10:c.387C>T
ENST00000619550.5:n.361C>T
ENST00000683148.1:n.363C>T
ENST00000683657.1:n.1511C>T
ENST00000316099.9:c.387C>T
ENST00000316099.8:c.387C>T
ENST00000316673.8:c.321C>T
ENST00000372920.1:c.*154C>T
ENST00000415691.2:c.387C>T
ENST00000443598.6:c.387C>T
ENST00000457232.5:c.321C>T
ENST00000609795.5:c.321C>T
ENST00000619550.4:c.312C>T
NM_000457.4:c.387C>T
NM_001030003.2:c.321C>T
NM_001030004.2:c.321C>T
NM_001258355.1:c.366C>T
NM_001287182.1:c.312C>T
NM_001287183.1:c.312C>T
NM_001287184.1:c.312C>T
NM_175914.4:c.321C>T
NM_178849.2:c.387C>T
NM_178850.2:c.387C>T
NM_001030003.3:c.321C>T
NM_001030004.3:c.321C>T
NM_001258355.2:c.366C>T
NM_001287182.2:c.312C>T
NM_001287184.2:c.312C>T
NM_178849.3:c.387C>T
NM_178850.3:c.387C>T
NM_000457.5:c.387C>T
NM_000457.6:c.387C>T
NM_001287183.2:c.312C>T

Likely Benign

Met criteria codes 2
BP4 BP7
Not Met criteria codes 2
PM2 BS1

Evidence Links 0

Expert Panel

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.321C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 107 (p.(Ala107=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.636, which is below the MDEP cutoff of 2.0) (BP4, BP7). ). The Popmax frequency of the c.321C>T variant in gnomAD v2.1.1 is 0.000007040, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.321C>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): BP4, BP7.
Met criteria codes
BP4
The computational splicing predictor SpliceAI gives a score of 0 for donor/acceptor loss, suggesting that the variant has no impact on splicing.
BP7
This variant is not predicted by SpliceAI to impact splicing (SpliceAI score of 0, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.636, which is below the MDEP cutoff of 2.0)
Not Met criteria codes
PM2
The Popmax frequency of the c.321C>T variant in gnomAD v2.1.1 is 0.000007040, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.
BS1
The Popmax frequency of the c.321C>T variant in gnomAD v2.1.1 is 0.000007040, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.
Approved on: 2023-01-12
Published on: 2023-01-12
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