rs193922591
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PS1_ModerateBP4_ModerateBS2
The NM_000545.8(HNF1A):āc.1854C>Gā(p.Ile618Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,992 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1854C>G | p.Ile618Met | missense_variant | 10/10 | ENST00000257555.11 | NP_000536.6 | |
C12orf43 | NM_022895.3 | c.*3003G>C | 3_prime_UTR_variant | 6/6 | ENST00000288757.7 | NP_075046.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1854C>G | p.Ile618Met | missense_variant | 10/10 | 1 | NM_000545.8 | ENSP00000257555.5 | ||
C12orf43 | ENST00000288757.7 | c.*3003G>C | 3_prime_UTR_variant | 6/6 | 1 | NM_022895.3 | ENSP00000288757.5 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152230Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250950Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135696
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461762Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11AN XY: 727170
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152230Hom.: 1 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 25, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 618 of the HNF1A protein (p.Ile618Met). This variant is present in population databases (rs193922591, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of HNF1A-related conditions (PMID: 10588527, 32238361). ClinVar contains an entry for this variant (Variation ID: 36813). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 27, 2020 | - - |
Maturity onset diabetes mellitus in young Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2018 | The p.I618M variant (also known as c.1854C>G), located in coding exon 10 of the HNF1A gene, results from a C to G substitution at nucleotide position 1854. The isoleucine at codon 618 is replaced by methionine, an amino acid with highly similar properties. This variant was identified in an individual diagnosed with diabetes at age 38; his mother also had diabetes, but was not analyzed (Ng MC et al. Diabet. Med., 1999 Nov;16:956-63). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Maturity-onset diabetes of the young type 3 Other:1
not provided, no classification provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at