TET2 c.4114_4131dupACTGCATGTTTGGACTTC, p.Thr1372_Phe1377dup
NM_001127208.2:c.4114_4131dupACTGCATGTTTGGACTTC
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
TET2
Transcript
NM_001127208.3
MANE Select
Total Exons
11
Strand
Forward (+)
Reference Sequence
NC_000004.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001127208.1 | Alternative | 11 exons | Forward |
| NM_001127208.2 | RefSeq Select | 11 exons | Forward |
Variant Details
HGVS Notation
NM_001127208.2:c.4114_4131dupACTGCATGTTTGGACTTC
Protein Change
T1372_F1377dup
Location
Exon 9
(Exon 9 of 11)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001127208.3
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Studies
Summary
The TET2 T1372_F1377dup variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
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 is a known mechanism of disease.' The evidence for this variant indicates an in-frame duplication (T1372_F1377dup) rather than a null effect. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
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 indication that the same amino acid change has been previously established as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
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.' There is no evidence of de novo occurrence provided for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines (and noting PTEN Pre-processing context), the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product.' The provided evidence indicates that the TET2 T1372_F1377dup variant has not been functionally characterized and no functional data supports a damaging effect. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
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 does not show an increased prevalence in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or a critical and well-established functional domain (e.g., active site of an enzyme) without benign variation.' The evidence does not indicate that the variant lies within such a critical region. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to Standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) in population databases such as Exome Sequencing Project, 1000 Genomes Project, or ExAC/gnomAD.' The evidence for this variant shows that it is absent from population databases (MAF = 0% and not found in gnomAD). Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' There is no evidence regarding the variant being in trans with a pathogenic variant for a recessive condition. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in‐frame deletions/insertions in a non-repeat region or stop-loss variants.' Although this variant results in a small in-frame duplication (protein length change), there is insufficient evidence that this alteration impacts protein function in a disease-contributing manner. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
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 does not indicate a novel missense change at a residue with a known pathogenic alternate; instead, it is an in-frame duplication. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' There is no evidence provided for a de novo event for this variant. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' There is no segregation evidence provided for this variant. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
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 variant in question is an in-frame duplication rather than a straightforward missense change and no evidence supports its pathogenicity through this mechanism. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
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, including SpliceAI predictions (score of 0), does not support a deleterious effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
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.' There is no information provided that indicates the patient’s phenotype is highly specific for a TET2-associated disorder. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible supporting evidence.' There is no reputable source that has reported this variant as pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (typically >5% in general population databases).' The evidence shows that the variant has a 0% frequency in population databases, so this rule is not applicable. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder.' Since the variant is absent from population databases, this criterion is not applicable. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
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.' There is no evidence that this variant has been observed in healthy individuals where full penetrance is expected. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing.' The variant has not been functionally characterized; thus, there is no well-established study to support a definitive benign effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The available evidence does not provide segregation data for this variant. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease.' The variant here is an in-frame duplication rather than a typical missense change, and there is no specific evidence to suggest this mechanism. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
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.' There is no evidence of such occurrence for this variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function.' Although the variant is an in-frame duplication, there is no clear evidence to indicate that it occurs in a repetitive region that is known to be benign. Therefore, this criterion is not applied.
BP4
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 (e.g., conservation, splicing impact, etc.).' The evidence for this variant includes computational analysis such as SpliceAI which yields a score of 0, indicating no expected impact on splicing. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' There is no evidence provided that suggests the variant is found in a case with an alternative molecular diagnosis. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence.' There is no such reputable source reporting this variant as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing.' This variant is not synonymous but an in-frame duplication, and therefore, this rule does not apply. Therefore, this criterion is not applied.