chr20-44424208-C-T
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_175914.5(HNF4A):c.1017C>T(p.Phe339=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )
Consequence
HNF4A
NM_175914.5 synonymous
NM_175914.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.02
Genes affected
HNF4A (HGNC:5024): (hepatocyte nuclear factor 4 alpha) The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
?
Variant 20-44424208-C-T is Benign according to our data. Variant chr20-44424208-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 586010.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
?
Synonymous conserved (PhyloP=-3.02 with no splicing effect.
BS2
?
High AC in GnomAdExome at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF4A | NM_175914.5 | c.1017C>T | p.Phe339= | synonymous_variant | 8/10 | ENST00000316673.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF4A | ENST00000316673.9 | c.1017C>T | p.Phe339= | synonymous_variant | 8/10 | 1 | NM_175914.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250470Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135510
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GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461726Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27AN XY: 727156
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ClinVar
Significance: Likely benign
Submissions summary: Benign:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 30, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2020 | - - |
Maturity onset diabetes mellitus in young Benign:1
Benign, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs142268325 in MODY, yet. - |
Monogenic diabetes Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Jan 12, 2023 | 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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
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RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at