chr12-120999627-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.1768C>G variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 590(p.(Arg583Gly)) of NM_000545.8. This variant has a minor allele frequency of 0.000009 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). In summary, c.1768C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386973441/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1768G>A | p.Val590Met | missense_variant, splice_region_variant | Exon 9 of 10 | ENST00000257555.11 | NP_000536.6 | |
HNF1A | NM_001306179.2 | c.1789G>A | p.Val597Met | missense_variant, splice_region_variant | Exon 9 of 10 | NP_001293108.2 | ||
HNF1A | NM_001406915.1 | c.1576G>A | p.Val526Met | missense_variant, splice_region_variant | Exon 8 of 9 | NP_001393844.1 | ||
HNF1A | XM_024449168.2 | c.1861G>A | p.Val621Met | missense_variant, splice_region_variant | Exon 8 of 9 | XP_024304936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1768G>A | p.Val590Met | missense_variant, splice_region_variant | Exon 9 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000420 AC: 1AN: 238240Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130248
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1456676Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 724638
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 16, 2017 | - - |
Monogenic diabetes Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Apr 17, 2022 | The c.1768C>G variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 590(p.(Arg583Gly)) of NM_000545.8. This variant has a minor allele frequency of 0.000009 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). In summary, c.1768C>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 30, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 590 of the HNF1A protein (p.Val590Met). This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (PMID: 33477506). ClinVar contains an entry for this variant (Variation ID: 447484). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Probably Damaging". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at