chr12-121001115-CAG-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000545.8(HNF1A):c.1822_1823del(p.Ser608ProfsTer40) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 33)
Consequence
HNF1A
NM_000545.8 frameshift
NM_000545.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.53
Genes affected
HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]
C12orf43 (HGNC:25719): (chromosome 12 open reading frame 43) Predicted to be involved in Spemann organizer formation and negative regulation of Wnt signaling pathway. Predicted to be located in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-121001115-CAG-C is Pathogenic according to our data. Variant chr12-121001115-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 1687086.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-121001115-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1822_1823del | p.Ser608ProfsTer40 | frameshift_variant | 10/10 | ENST00000257555.11 | |
C12orf43 | NM_022895.3 | c.*3036_*3037del | 3_prime_UTR_variant | 6/6 | ENST00000288757.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1822_1823del | p.Ser608ProfsTer40 | frameshift_variant | 10/10 | 1 | NM_000545.8 | P4 | |
C12orf43 | ENST00000288757.7 | c.*3036_*3037del | 3_prime_UTR_variant | 6/6 | 1 | NM_022895.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | May 09, 2022 | The c.1822_1823delAG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 608 (NM_000545.8), adding 40 novel amino acids before encountering a stop codon (p.(Ser608ProfsTer40)). While this variant, located 5' of c.1854 in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong). This variant was identified in eight unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant segregated with diabetes, with 8 informative meioses in two families with MODY (PP1_Strong; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, this variant was identified in at least three individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors). In summary, c.1822_1823delAG meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1 approved 9/30/21): PVS1_Strong, PS4, PP1_Strong, PM2_Supporting, PP4_Moderate. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.