12-120994244-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP3_StrongPP5_Strong
The NM_000545.8(HNF1A):c.794A>G(p.Tyr265Cys) 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y265S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.794A>G | p.Tyr265Cys | missense_variant | 4/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.794A>G | p.Tyr265Cys | missense_variant | 4/10 | ||
HNF1A | NM_001406915.1 | c.794A>G | p.Tyr265Cys | missense_variant | 4/9 | ||
HNF1A | XM_024449168.2 | c.794A>G | p.Tyr265Cys | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.794A>G | p.Tyr265Cys | missense_variant | 4/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 29, 2020 | DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.794A>G, in exon 4 that results in an amino acid change, p.Tyr265Cys. This sequence change has been previously described in a patient with pre gestational diabetes mellitus who also carried another previously reported missense variant, c.862G>T, in the same gene (PMID: 30663027). This sequence change is absent from the large population databases (ExAC and gnomAD). The p.Tyr265Cys change affects a highly conserved amino acid residue located in a homeobox domain of the HNF1A protein that is known to be functional. The p.Tyr265Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). - |
Monogenic diabetes Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | May 02, 2022 | The c.794A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 265 (p.Tyr265Cys) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant also is predicted to be deleterious by computational evidence, with a REVEL score of 0.941, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 30663027, internal lab contributors). Another missense variant, c.794A>C (p.Tyr265Ser), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.794A>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 9/30/2021): PM1, PP3, PM2_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.