17-37744641-C-T
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_000458.4(HNF1B):c.244G>A(p.Asp82Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,612,540 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000458.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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HNF1B | ENST00000617811.5 | c.244G>A | p.Asp82Asn | missense_variant | Exon 1 of 9 | 1 | NM_000458.4 | ENSP00000480291.1 | ||
HNF1B | ENST00000621123.4 | c.244G>A | p.Asp82Asn | missense_variant | Exon 1 of 9 | 1 | ENSP00000482711.1 | |||
HNF1B | ENST00000613727.4 | c.244G>A | p.Asp82Asn | missense_variant | Exon 1 of 7 | 1 | ENSP00000477524.1 | |||
HNF1B | ENST00000614313.4 | c.244G>A | p.Asp82Asn | missense_variant | Exon 1 of 8 | 5 | ENSP00000482529.1 |
Frequencies
GnomAD3 genomes AF: 0.000676 AC: 103AN: 152272Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000616 AC: 154AN: 249854Hom.: 0 AF XY: 0.000620 AC XY: 84AN XY: 135432
GnomAD4 exome AF: 0.000964 AC: 1407AN: 1460150Hom.: 1 Cov.: 35 AF XY: 0.000965 AC XY: 701AN XY: 726456
GnomAD4 genome AF: 0.000676 AC: 103AN: 152390Hom.: 0 Cov.: 33 AF XY: 0.000617 AC XY: 46AN XY: 74522
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:4
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HNF1B: BS1:Supporting, BS2 -
Reported in unrelated patients in published literature, including one individual with hyperuricemia, bilateral renal cysts and dysplasia, and stage 1 chronic kidney disease and an individual whose clinical information was not provided (PMID: 30666461, 31264968); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19639018, 26899772, 24897035, 27634015, 31264968, 34426522, 32041611, 30666461, 38025229, 30476936) -
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Renal cysts and diabetes syndrome Uncertain:1Benign:1
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not specified Uncertain:1Benign:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified in HGMD as DM, related to HNF1B-related disease (reported in one patient, phenotype not specified). This variant is classified in ClinVar with 1 star as VUS by Emory. It is present in ExAC with a Max MAF of 0.12%. -
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HNF1B-related disorder Uncertain:1
The HNF1B c.244G>A variant is predicted to result in the amino acid substitution p.Asp82Asn. This variant has been reported in patients with features of HNF1B-related disorders; however, pathogenicity has not been established (Faguer et al. 2014. PubMed ID: 24897035; Brahm et al. 2016. PubMed ID: 27634015; Yu et al. 2019. PubMed ID: 31264968, supplementary table 6; Okorn et al. 2019. PubMed ID: 30666461; Kanda et al. 2016. PubMed ID: 26899772; Zuber et al. 2009. PubMed ID: 19639018). This variant is reported in 0.11% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which is likely too common to be a primary cause of autosomal dominant disorders. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Monogenic diabetes Uncertain:1
ACMG criteria: PP3 (REVEL 0.890 + 7 predictors); PP4 (19639018, 26899772; variant also identified in patient in PMID: 24897035 (no clinical info, can't tell if overlap with other papers); BS2 (12 cases and 15 controls in T2Dgenes); BS1 (MAF in gnomAD EurNF population is 0.09%; 0.14% in ESP European pop)= scores as benign, but going to call as VUS given case reports and predictors (conflicting evidence). -
Autosomal dominant polycystic liver disease Uncertain:1
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Maturity onset diabetes mellitus in young Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at