rs754306821
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_000545.8(HNF1A):c.923C>T(p.Pro308Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,594,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain risk allele (★★).
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.923C>T | p.Pro308Leu | missense_variant | Exon 4 of 10 | ENST00000257555.11 | NP_000536.6 | |
HNF1A | NM_001306179.2 | c.923C>T | p.Pro308Leu | missense_variant | Exon 4 of 10 | NP_001293108.2 | ||
HNF1A | NM_001406915.1 | c.923C>T | p.Pro308Leu | missense_variant | Exon 4 of 9 | NP_001393844.1 | ||
HNF1A | XM_024449168.2 | c.923C>T | p.Pro308Leu | missense_variant | Exon 4 of 9 | XP_024304936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.923C>T | p.Pro308Leu | missense_variant | Exon 4 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000281 AC: 6AN: 213210Hom.: 0 AF XY: 0.0000348 AC XY: 4AN XY: 114832
GnomAD4 exome AF: 0.00000971 AC: 14AN: 1441854Hom.: 0 Cov.: 35 AF XY: 0.00000979 AC XY: 7AN XY: 715308
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
not specified Uncertain: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: Variant seen in 1 affected patient in HGMD. Max MAF of 0.03% in ExAC. -
Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Uncertain:1
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not provided Uncertain:1
This missense change has been observed in individual(s) with clinical features of autosomal dominant maturity-onset diabetes of the young (PMID: 18003757). This sequence change replaces proline with leucine at codon 308 of the HNF1A protein (p.Pro308Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs754306821, ExAC 0.03%). ClinVar contains an entry for this variant (Variation ID: 402948). 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 HNF1A protein function. 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. -
Maturity-onset diabetes of the young type 3 Uncertain:1
The c.923C>T variant in the HNF1A gene has not been previously described in patients with diabetes MODY to our knowledge. The variants has a very low frequency in gnomAD 4.0 (AF=1.0664e-05) (PM2) and REVEL value is 0.687 (PP3). With all the available evidence, the variant is classified as of unknown significance. -
Maturity onset diabetes mellitus in young Other:1
Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs754306821 with MODY3. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at