chr20-44355852-C-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_175914.5(HNF4A):c.48C>G(p.Tyr16Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_175914.5 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF4A | NM_175914.5 | c.48C>G | p.Tyr16Ter | stop_gained, splice_region_variant | 1/10 | ENST00000316673.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF4A | ENST00000316673.9 | c.48C>G | p.Tyr16Ter | stop_gained, splice_region_variant | 1/10 | 1 | NM_175914.5 | ||
HNF4A | ENST00000457232.5 | c.48C>G | p.Tyr16Ter | stop_gained, splice_region_variant | 1/10 | 1 | |||
HNF4A | ENST00000609795.5 | c.48C>G | p.Tyr16Ter | stop_gained, splice_region_variant | 1/8 | 1 | |||
HNF4A | ENST00000609262.5 | c.-184C>G | splice_region_variant, 5_prime_UTR_variant | 1/4 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Maturity-onset diabetes of the young type 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Exeter Molecular Genetics Laboratory | Oct 05, 2021 | The c.48C>G variant in the HNF4 homeobox A gene, HNF4A, Results in the substitution of a tyrosine amino acid to a termination codon (p.Tyr16Ter) in exon 1 of the pancreatic specific HNF4A isoform NM_175914.5. This variant is predicted to generate an mRNA with a premature termination codon that would undergo nonsense mediated decay resulting in absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Very Strong; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified by our laboratory in an individual with clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate). This variant also segregated with diabetes in this family with 7 informative meioses (PP1_Strong). In summary, c.48C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied: PVS1_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting. - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Jan 22, 2024 | The c.48C>G variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 16 (p.(Tyr16*)) of NM_175914.5. This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes/neonatal hyperinsulinism, with 13 informative meioses in 2 families (PP1_Strong; internal lab contributors). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes or diazoxide-responsive hyperinsulinemic hypoglycemia; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 20164212, 16917892, 17407387, 18268044, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea-responsive) (PP4_Moderate; internal lab contributors). In summary, c.48C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP1_Strong, PP4_Moderate, PM2_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.