chr20-44355726-C-T
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_175914.5(HNF4A):c.-79C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,308,684 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00043 ( 6 hom. )
Consequence
HNF4A
NM_175914.5 5_prime_UTR
NM_175914.5 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.578
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 -7 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.31).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00021 (32/152376) while in subpopulation SAS AF= 0.00497 (24/4826). AF 95% confidence interval is 0.00343. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 32 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| HNF4A | NM_175914.5 | c.-79C>T | 5_prime_UTR_variant | 1/10 | ENST00000316673.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HNF4A | ENST00000316673.9 | c.-79C>T | 5_prime_UTR_variant | 1/10 | 1 | NM_175914.5 |
Frequencies
GnomAD3 genomes 0.000210 AC: 32AN: 152258Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.000429 AC: 496AN: 1156308Hom.: 6 Cov.: 16 AF XY: 0.000560 AC XY: 330AN XY: 589248
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GnomAD4 genome 0.000210 AC: 32AN: 152376Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74522
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 21, 2023 | This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this variant does not significantly alter or has an unclear effect on HNF4A gene expression (PMID: 12242469). ClinVar contains an entry for this variant (Variation ID: 1442643). This variant has been observed in individual(s) with HNF4A-related conditions, however it has also been observed in unaffected controls (PMID: 12242469, 21062274). This variant occurs in a non-coding region of the HNF4A gene. It does not change the encoded amino acid sequence of the HNF4A protein. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2024 | Observed in two unrelated individuals in published literature with maturity onset diabetes of the young (MODY); however, the variant did not segregate completely with the condition in the family of one proband and familial segregation information was not provided for the other proband (PMID: 12242469, 21062274); In-silico analysis and one published study are inconclusive as to whether the variant alters gene function (PMID: 12242469). In the absence of additional RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 12242469, 23014256, 21062274) - |
Type 2 diabetes mellitus;C1852093:Maturity-onset diabetes of the young type 1;C4014962:Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 19, 2022 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at