chr12-121001098-C-CA
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_000545.8(HNF1A):c.1803dup(p.Asp602ArgfsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Genomes: not found (cov: 33)
Consequence
HNF1A
NM_000545.8 frameshift
NM_000545.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.17
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 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 7 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1803dup | p.Asp602ArgfsTer47 | frameshift_variant | 10/10 | ENST00000257555.11 | |
C12orf43 | NM_022895.3 | c.*3054_*3055insT | 3_prime_UTR_variant | 6/6 | ENST00000288757.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1803dup | p.Asp602ArgfsTer47 | frameshift_variant | 10/10 | 1 | NM_000545.8 | P4 | |
C12orf43 | ENST00000288757.7 | c.*3054_*3055insT | 3_prime_UTR_variant | 6/6 | 1 | NM_022895.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Monogenic diabetes Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | May 04, 2022 | The c.1803dupA variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 602 (NM_000545.8), adding 47 novel amino acids before encountering a stop codon (p.(Asp602ArgefsTer47)). While this variant, located 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). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of information about when insulin treatment was initiated, and HNF4A was not tested (internal lab contributors). Therefore, PP4 cannot be applied. In summary, c.1803dupA 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): PVS1_Strong, PM2_Supporting. - |
Computational scores
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Splicing
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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.