TET2 c.3523A>G, p.Ile1175Val
NM_001127208.2:c.3523A>G
COSM43506
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
0.125
Likely Benign
COSMIC Recurrence
1 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.3523A>G
Protein Change
I1175V
Location
Exon 5
(Exon 5 of 11)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1175 in gene TET2
Alternate Identifiers
COSM43506
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
No evidence of other pathogenic variants at position 1175 in gene TET2
Functional Studies
Summary
The TET2 I1175V variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.125
0.125
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.00
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
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 an amino acid substitution (I1175V) rather than a null variant. Therefore, this criterion is not applied at any strength.
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 does not document any previously established pathogenic variant with the same amino acid change. 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'. The evidence for this variant does not include any de novo confirmation. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing guidelines, the rule/finding for PS3 is: 'The TET2 I1175V variant has not been functionally characterized, and its biological significance remains unknown'. The evidence shows no well‐established functional studies demonstrating 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 or well-established functional domain without benign variation'. The evidence for this variant does not indicate localization to such a domain. 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)' as seen in population databases. The evidence for this variant shows a MAF of 0% and it is 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: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant does not include any data regarding in trans occurrence with another pathogenic variant. 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 or stop-loss variants'. The evidence for this variant is a missense change rather than an in-frame indel or stop-loss variant. 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 any other pathogenic substitution at position I1175. 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'. The evidence for this variant does not include any de novo data. 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'. The evidence for this variant does not include family segregation data. 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 evidence for this variant does not provide supportive indication that missense changes in TET2 are predominantly pathogenic. 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/gene product'. The evidence for this variant includes in silico predictions (REVEL = 0.12, CADD = 3.00, SpliceAI = 0.00) that are benign, which is instead used for BP4. 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 highly specific for a disease with a single genetic etiology'. The evidence for this variant does not include any relevant clinical phenotype information specific to TET2-related disease. 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 evidence'. The evidence for this variant shows no such report in databases such as ClinVar. 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 (based on population data)'. The evidence for this variant shows a population frequency of 0%, which does not meet BA1 requirements. 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 disorder'. The evidence for this variant demonstrates absence from large population datasets, thus BS1 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'. The evidence for this variant does not include such observations. 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 evidence for this variant confirms that functional studies have not been performed. 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 evidence for this variant does not include segregation data. 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 where only LoF causes disease'. The evidence for this variant does not specifically support this scenario. 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'. The evidence for this variant does not include any such observations. 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'. The evidence for this variant is a missense change rather than an in-frame indel in a repetitive region. 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, evolutionary, splicing impact)'. The evidence for this variant includes a REVEL score of 0.12, CADD score of 3.00, and SpliceAI scores of 0.00, all of which support a benign interpretation. 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'. The evidence for this variant does not provide any such alternate explanation. 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'. The evidence for this variant does not include such a report. 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'. The evidence for this variant is a missense change and not a synonymous variant. Therefore, this criterion is not applied.