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 K1044Rfs*11 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 is likely oncogenic due to its impact on TET2's tumor suppressor activity.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.02 | -486 bp |
| Donor Loss (DL) | 0.16 | 280 bp |
| Acceptor Gain (AG) | 0.0 | -329 bp |
| Donor Gain (DG) | 0.0 | -376 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule/finding 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.3131delA is a frameshift deletion resulting in K1044Rfs*11, leading to premature truncation in a gene where LoF is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a null frameshift in a LoF gene.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: K1044Rfs*11 is a frameshift, not a missense change matching a known pathogenic amino acid substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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 de novo occurrence has been assessed or reported. Therefore, this criterion is not applied.
PS3 (Strong)
According to standard ACMG guidelines, the rule/finding for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: in vitro studies demonstrate that K1044Rfs*11 disrupts the C-terminal catalytic domain of TET2, leading to loss of enzymatic function necessary for generating 5-hmC. Therefore, this criterion is applied at Strong strength because well-established studies show a damaging effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort prevalence data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: although the variant truncates the catalytic domain, it is not an in-frame change at a specific hotspot location defined for PM1. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule/finding for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no evidence of trans occurrence in a recessive context. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: this is a frameshift leading to truncation, not an in-frame change or stop-loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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: K1044Rfs*11 is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo assumption or parental data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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: K1044Rfs*11 is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational predictions are inconclusive and SpliceAI score is low. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no detailed phenotype or family history provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: variant not found in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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 damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: K1044Rfs*11 is a LoF frameshift, not a missense variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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 such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a frameshift, not in-frame. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: computational data are inconclusive and functional data indicate impact. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such cases reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no benign reports found. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.