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) | 0.0 | 11 bp |
| Donor Loss (DL) | 0.0 | 72 bp |
| Acceptor Gain (AG) | 0.01 | -27 bp |
| Donor Gain (DG) | 0.0 | 54 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LoF) is a known mechanism of disease. The evidence for this variant shows: c.3731T>G results in a missense change (L1244R), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. The evidence for this variant shows: No previously established pathogenic variant resulting in p.L1244R has been reported. 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: No parental testing or de novo status data available. 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 for L1244R. 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 cohort 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 hotspot or well-established functional domain without benign variation. The evidence for this variant shows: No data indicating that residue L1244 lies within a known hotspot or critical functional 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: c.3731T>G is absent from population databases including gnomAD (MAF = 0%). Therefore, this criterion is applied at Moderate strength.
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: TET2‐related disease is dominant and no trans data exist. 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: L1244R is a missense change with no protein length alteration. 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 missense changes reported at residue L1244. 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: No de novo assumption data. 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 variation and where missense variants are a common mechanism of disease. The evidence for this variant shows: TET2 disease mechanism is loss of function rather than missense. Therefore, this criterion is not applied.
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: In silico predictions are mixed (REVEL 0.71 suggests possible impact, but CADD 4.32 is low and SpliceAI 0.01 indicates no splicing effect), overall not concordant for deleterious. Therefore, this criterion is not applied.
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 clinical phenotype data provided. 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 exist. 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: 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 the disorder. The evidence for this variant shows: Absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: Observed in healthy individuals for a dominant disorder 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: No functional assays performed. 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 (Supporting)
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: TET2 disease mechanism is established as haploinsufficiency/LoF, and L1244R is a missense change. Therefore, this criterion is applied at Supporting strength.
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: L1244R is a missense substitution. Therefore, this criterion is not applied.
BP4 (Supporting)
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: CADD score is low (4.32), SpliceAI predicts no splicing impact (0.01), and overall computational predictions are not concordant for damaging effect. Therefore, this criterion is applied at Supporting strength.
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 case reports. 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. 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: L1244R is a missense variant. Therefore, this criterion is not applied.