Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001127208.3 | MANE Select | 9589 nt | 297–6305 |
| NM_001127208.1 | Alternative | 9677 nt | 387–6395 |
| NM_001127208.2 | RefSeq Select | 9796 nt | 488–6496 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The TET2 Q1009* variant is a truncating mutation that disrupts the C-terminal catalytic domain of the TET2 protein. This disruption is predicted to inactivate the gene, leading to a loss of enzymatic function necessary for generating 5-hydroxymethylcytosine (5-hmC). Functional evidence supports that this variant has a damaging effect, contributing to oncogenic processes.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -150 bp |
| Donor Loss (DL) | 0.03 | 384 bp |
| Acceptor Gain (AG) | 0.02 | -382 bp |
| Donor Gain (DG) | 0.02 | -272 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: NM_001127208.2:c.3025C>T creates a premature stop codon (Q1009*) predicted to result in loss of the C-terminal catalytic domain of TET2, and loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where LoF is established as pathogenic.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: there is no reported pathogenic variant causing the same Q1009* change by an alternate nucleotide. Therefore, this criterion is not applied because there is no known identical amino acid change documented as pathogenic.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no parental testing or de novo status information is available. Therefore, this criterion is not applied due to lack of confirmed de novo data.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: functional studies demonstrate that Q1009* truncates the catalytic domain of TET2, abolishing 5-hydroxymethylcytosine generation and impairing enzymatic activity. Therefore, this criterion is applied at Strong strength because well-established functional assays confirm a damaging effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals is significantly increased compared with controls". The evidence for this variant shows: no case-control frequency data or statistical enrichment analysis is available. Therefore, this criterion is not applied due to lack of prevalence data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: while the C-terminal domain is functional, PM1 is intended for missense variants at hotspots; this is a truncating variant. Therefore, this criterion is not applied because the variant is a nonsense change and not a missense hotspot.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: it is absent from gnomAD and other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is not observed in population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant". The evidence for this variant shows: inheritance and trans status are not applicable or not assessed. Therefore, this criterion is not applied due to absence of relevant trans or recessive inheritance data.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a premature stop variant causing truncation, not an in-frame indel or stop-loss. Therefore, this criterion is not applied because the variant type does not match PM4.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: it is a nonsense variant, not a missense change. Therefore, this criterion is not applied because PM5 applies only to missense variants.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo or parental data are available. Therefore, this criterion is not applied due to absence of de novo assumptions.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data are provided. Therefore, this criterion is not applied due to lack of segregation information.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: it is a nonsense change, not missense. Therefore, this criterion is not applied because PP2 is specific to missense variants.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational/splicing predictions are inconclusive or minimal for splicing, and the impact is driven by truncation. Therefore, this criterion is not applied because in silico data do not add independent support beyond PVS1/PS3.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no detailed phenotype or clinical context is provided. Therefore, this criterion is not applied due to absence of phenotype specificity data.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: it is not listed in ClinVar or other reputable databases. Therefore, this criterion is not applied because no such reports exist.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The evidence for this variant shows: it is absent in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no observations in healthy individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: functional studies demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease". The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no cis/trans data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a nonsense change. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: computational predictions are minimal for splicing but do not negate the truncating effect. Therefore, this criterion is not applied because computational data do not override loss-of-function evidence.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such alternate molecular basis is documented. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no benign reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied.