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TET2c.5920A>CUncertain significance
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Variant interpretation report

TET2 c.5920A>C, p.(Arg1974=)

NM_001127208.2:c.5920A>C NP_001120680.1:p.(Arg1974=) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About TET2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_001127208.2:c.5920A>C is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (AF=0.00019%, 3/1,551,980 alleles, 0 homozygotes; grpmax FAF=7e-07), well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 1 met · 6 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001127208.2:c.5920A>C (p.Arg1974=) is a synonymous variant in TET2. It is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=0.00019%, 3/1,551,980 alleles, 0 homozygotes), meeting PM2 at supporting level. No other pathogenic or benign criteria are met. Per generic ACMG/AMP 2015 classification rules (PMID:25741868), a single supporting criterion (PM2) is insufficient to reach Likely Pathogenic or Likely Benign classification thresholds. This variant is classified as a Variant of Uncertain Significance (VUS).

SpliceAI predicts no splice impact (max delta score = 0.00). Computational predictors REVEL and BayesDel are unavailable for this synonymous variant. Conservation data are unavailable, precluding application of BP7 despite the clean SpliceAI result.

This variant is absent from ClinVar and has not been reported in any publication identified through literature search. TET2 germline loss-of-function variants are associated with an ALPS-like phenotype and hematologic malignancy predisposition, but the clinical significance of synonymous variants in this gene remains uncertain.

Met · 1

PM2 SupportingNM_001127208.2:c.5920A>C is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (AF=0.00019%, 3/1,551,980 alleles, 0 homozygotes; grpmax FAF=7e-07), well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • gnomAD v4.1: AF=1.93e-06 (3/1
  • 551
  • 980 alleles
  • 0 homozygotes)
  • grpmax FAF=7e-07.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 6 · evaluated, threshold not reached

PM1 This variant does not lie in a statistically significant mutational hotspot in TET2, and the affected residue (Arg1974) has not been identified as a critical functional domain with a paucity of benign variation. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis confirms variant is not in a statistically significant hotspot region.
PP3 Multiple lines of computational evidence are required to support a deleterious effect. SpliceAI predicts no splice impact (max delta=0.00), and REVEL, BayesDel, and HCI prior scores are all unavailable for this variant. No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00 (no splice impact).
  • REVEL score unavailable.
  • BayesDel score unavailable.
  • HCI prior score unavailable.
Still missing
  • REVEL
  • BayesDel
  • and conservation scores unavailable for this synonymous variant.
Sources
spliceai ↗
BA1 The variant allele frequency in gnomAD v4.1 is 0.00019% (3/1,551,980 alleles), far below the 1% threshold for BA1. The variant does not qualify as a common polymorphism. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=0.00019%
  • well below BA1 threshold of 1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant allele frequency in gnomAD v4.1 is 0.00019% (3/1,551,980 alleles), far below the 0.3% threshold for BS1. The variant is also absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=0.00019%
  • well below BS1 threshold of 0.3%.
  • Absent from gnomAD v2.1 and gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. Only one line is available: SpliceAI predicts no splice impact (max delta=0.00). REVEL, BayesDel, and conservation data are all unavailable, precluding a multi-line benign computational assessment. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00 (no splice impact).
  • REVEL
  • BayesDel
  • and conservation scores unavailable.
Still missing
  • Additional computational predictors (REVEL
  • BayesDel
  • conservation) unavailable to satisfy 'multiple lines' requirement.
Sources
spliceai ↗
BP7 BP7 requires a synonymous variant for which splicing prediction algorithms predict no splice impact AND the nucleotide is not highly conserved. SpliceAI confirms no predicted splice impact (max delta=0.00), satisfying the first condition. However, nucleotide-level conservation data (e.g., phyloP, GERP) are unavailable, preventing confirmation that the nucleotide is not highly conserved — a required component of BP7. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Arg1974=).
  • SpliceAI max delta=0.00 confirms no predicted splice impact.
  • Nucleotide conservation data unavailable.
Still missing
  • Nucleotide-level conservation scores (phyloP
  • GERP) needed to confirm the residue is not highly conserved
  • if not conserved
  • BP7 would be applicable at supporting benign level.
Sources
spliceai ↗

Not assessed · 15 · no assessment recorded

PS1 PS1 requires a different nucleotide change at the same amino acid position as an established pathogenic variant. This variant is synonymous (no amino acid change), and no pathogenic variants at residue Arg1974 are available for comparison. Details ▾Hide ▴
Still missing
  • No established pathogenic variants at Arg1974 for comparator analysis.
PS2 No de novo data (with confirmed paternity and maternity) are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo occurrence data available.
PS3 No well-established in vitro or in vivo functional studies have been identified for NM_001127208.2:c.5920A>C. Details ▾Hide ▴
Still missing
  • No functional studies available for this synonymous variant.
PS4 No case-control studies comparing variant prevalence in affected individuals versus controls are available. Details ▾Hide ▴
Still missing
  • No case-control or aggregate prevalence data available.
PM6 No de novo occurrence data (without confirmation of paternity and maternity) are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No cosegregation data with disease in multiple affected family members are available. Details ▾Hide ▴
Still missing
  • No family cosegregation data available.
PP4 No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for TET2-related disease. Details ▾Hide ▴
Still missing
  • No patient phenotype or clinical history provided.
PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and is not classified in any published literature. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar.
Sources
clinvar ↗
BS2 No data are available on whether the 3 individuals carrying this variant in gnomAD v4.1 are healthy adults, which would be required to apply BS2 (observed in a healthy adult individual for a recessive/highly penetrant disorder with full penetrance expected at an early age). Details ▾Hide ▴
Still missing
  • No phenotype data available for gnomAD carriers.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been identified for this variant. Details ▾Hide ▴
Still missing
  • No functional studies available.
BS4 No family segregation data demonstrating lack of cosegregation with disease are available. Details ▾Hide ▴
Still missing
  • No family nonsegregation data available.
BP2 No data are available on whether this variant has been observed in trans with a known pathogenic TET2 variant. Details ▾Hide ▴
Still missing
  • No trans-phase data available.
BP5 No data are available on whether this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available.
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar.
Sources
clinvar ↗
PS5 No reputable source has independently classified this variant as pathogenic. The variant is absent from ClinVar and no published literature reports it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar.
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001127208.2:c.5920A>C is a synonymous variant (p.Arg1974=) with SpliceAI max delta score of 0.00 and no predicted splice impact. It does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus) and is therefore not eligible for PVS1 under the ClinGen SVI PVS1 decision framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Arg1974=)
  • SpliceAI max delta=0.00 confirms no splice alteration.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗spliceai ↗
PM3 N/APM3 applies to variants observed in trans with a pathogenic variant in recessive disorders. TET2 germline disease is not recessively inherited; this criterion is not applicable. Details ▾Hide ▴
Evidence considered
  • TET2-associated germline disease is not recessively inherited.
PM4 N/APM4 applies to non-repeat indels or stop-loss variants causing protein length changes. This is a single-nucleotide substitution; PM4 is not applicable. Details ▾Hide ▴
Evidence considered
  • Single-nucleotide substitution
  • PM4 is restricted to protein-length-altering variants.
PM5 N/APM5 requires a novel missense change at the same amino acid residue as an established pathogenic missense variant. NM_001127208.2:c.5920A>C is synonymous (p.Arg1974=) with no amino acid change, so no pathogenic comparator at this residue can be evaluated. Details ▾Hide ▴
Evidence considered
  • Synonymous variant produces no amino acid change
  • pm5_candidates confirms PM5 is not eligible.
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This is a synonymous variant and does not qualify for PP2 assessment. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • PP2 is restricted to missense variants.
BP1 N/ABP1 applies specifically to missense variants in genes where a truncating mechanism is the primary cause of disease. This is a synonymous variant and does not qualify for BP1 assessment. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • BP1 is restricted to missense variants.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
TET2
Transcript
NM_001127208.2
Coding (HGVS c.)
NM_001127208.2:c.5920A>C
Protein (HGVS p.)
NP_001120680.1:p.(Arg1974=)
GRCh38
chr4:105276430 A>C
GRCh37
chr4:106197587 A>C

Gene diagram

Every interpreted variant in TET2, mapped onto the exon structure of NM_001127208.2. Select a row to find it on the plot.

TET2NM_001127208.2
Fetching transcript structure from UCSC…
gnomAD v4.1 3 / 1,551,980 alleles AF 1.93e-06 · 0 homozygotes · FAF 7e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,551,980 alleles · 0 hom · FAF 7e-07
European (non-Finnish)3 / 1,147,046 2.6e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.93301e-06; MAF= 0.00019%, 3/1551980 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.61541e-06; MAF= 0.00026%, 3/1147046 alleles, homozygotes = 0); grpmax FAF= 7e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +2 bp
0.000
SpliceAI acceptor gainat -210 bp
0.000
SpliceAI donor lossat +7 bp
0.000
SpliceAI donor gainat +29 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.050

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Multiple lines of computational evidence are required to support a deleterious effect. SpliceAI predicts no splice impact (max delta=0.00), and REVEL, BayesDel, and HCI prior scores are all unavailable for this variant. No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00 (no splice impact).
  • REVEL score unavailable.
  • BayesDel score unavailable.
  • HCI prior score unavailable.
Still missing
  • REVEL
  • BayesDel
  • and conservation scores unavailable for this synonymous variant.
Sources
spliceai ↗
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. Only one line is available: SpliceAI predicts no splice impact (max delta=0.00). REVEL, BayesDel, and conservation data are all unavailable, precluding a multi-line benign computational assessment. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00 (no splice impact).
  • REVEL
  • BayesDel
  • and conservation scores unavailable.
Still missing
  • Additional computational predictors (REVEL
  • BayesDel
  • conservation) unavailable to satisfy 'multiple lines' requirement.
Sources
spliceai ↗
BP7 BP7 requires a synonymous variant for which splicing prediction algorithms predict no splice impact AND the nucleotide is not highly conserved. SpliceAI confirms no predicted splice impact (max delta=0.00), satisfying the first condition. However, nucleotide-level conservation data (e.g., phyloP, GERP) are unavailable, preventing confirmation that the nucleotide is not highly conserved — a required component of BP7. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Arg1974=).
  • SpliceAI max delta=0.00 confirms no predicted splice impact.
  • Nucleotide conservation data unavailable.
Still missing
  • Nucleotide-level conservation scores (phyloP
  • GERP) needed to confirm the residue is not highly conserved
  • if not conserved
  • BP7 would be applicable at supporting benign level.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 3 / 1,551,980 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.93301e-06; MAF= 0.00019%, 3/1551980 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.61541e-06; MAF= 0.00026%, 3/1147046 alleles, homozygotes = 0); grpmax FAF= 7e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.