rs886043813
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000458.4(HNF1B):c.884G>A(p.Arg295His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R295C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000458.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1B | NM_000458.4 | c.884G>A | p.Arg295His | missense_variant | 4/9 | ENST00000617811.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1B | ENST00000617811.5 | c.884G>A | p.Arg295His | missense_variant | 4/9 | 1 | NM_000458.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 25, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg295 amino acid residue in HNF1B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16249435, 23979948, 31825128). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 295 of the HNF1B protein (p.Arg295His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with HNF1B-related disorders and/or renal cysts and diabetes syndrome (PMID: 15068978, 16249435, 31131422, 33574344). ClinVar contains an entry for this variant (Variation ID: 288154). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1B protein function. Experimental studies have shown that this missense change affects HNF1B function (PMID: 15509593). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16249435, 17924661, 34487217, 27838256, 15068978, 31131422, 31595705, Weckwerth2021[paper], 33574344, 34440516, 15509593) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 14, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 22, 2018 | Not found in the total gnomAD dataset, and the data is high quality (0/276870 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. - |
Renal cysts and diabetes syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province | Jan 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | literature only | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Jul 06, 2019 | - - |
Type 2 diabetes mellitus;C0431693:Renal cysts and diabetes syndrome;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at