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
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.92 | -90 bp |
| Donor Loss (DL) | 0.85 | 0 bp |
| Acceptor Gain (AG) | 0.0 | 22 bp |
| Donor Gain (DG) | 0.0 | 421 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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. The evidence for this variant shows: it is a missense change (R1167T), not a null variant. Therefore, this criterion is not applied because the variant does not meet the null variant definition.
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 known pathogenic variant causing the same R1167 amino acid change. Therefore, this criterion is not applied.
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: de novo status is unknown. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: Well-established functional studies supportive of a damaging effect on the gene or gene product. The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: Prevalence in affected individuals significantly increased compared with controls. The evidence for this variant shows: no case-control or segregation data available. Therefore, this criterion is not applied.
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: R1167 is not reported as part of a known hotspot or critical domain. Therefore, this criterion is not applied.
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 not found in gnomAD and 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 for PM3 is: Detected in trans with a pathogenic variant (for recessive disorders). The evidence for this variant shows: no trans observations with a pathogenic variant reported. Therefore, this criterion is not applied.
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 missense substitution without change in protein length. Therefore, this criterion is not applied.
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: no other pathogenic variants reported at R1167. Therefore, this criterion is not applied.
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: de novo status is unknown. Therefore, this criterion is not applied.
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 segregation data available. Therefore, this criterion is not applied.
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: TET2 is primarily associated with loss-of-function mechanisms rather than missense. Therefore, this criterion is not applied.
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. The evidence for this variant shows: SpliceAI predicts a high impact on splicing (score 0.92) despite mixed other in silico scores. Therefore, this criterion is applied at Supporting strength because computational tools indicate a potential deleterious effect on splicing.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule 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 phenotype or family history specificity reported. Therefore, this criterion is not applied.
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: no such reports found. Therefore, this criterion is not applied.
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: allele frequency is 0%. 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 the disorder. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age. The evidence for this variant shows: no such observations reported. 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: no functional studies available. 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: while TET2 is primarily a loss-of-function gene, this specific missense variant may affect splicing. 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 a dominant disorder 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 for BP3 is: In-frame deletions/insertions in a repetitive region without known function. The evidence for this variant shows: it is a missense change, not an in-frame indel. 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 mixed with a strong splicing impact prediction. Therefore, this criterion is not applied.
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 alternate molecular basis reported. 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 such 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 missense substitution, not synonymous. Therefore, this criterion is not applied.