NM_001127208.2:c.1413C>T (p.Ser471=) is a synonymous variant in TET2 at extremely low population frequency (gnomAD v2.1 AF=0.00142%, 4/282,248 alleles; v4.1 AF=0.00056%, 9/1,614,034 alleles), meeting PM2 at supporting level.1 SpliceAI predicts no splicing impact (max delta=0.00), meeting BP7 (supporting benign) for a synonymous variant without predicted splice alteration.2 ClinVar contains a single submission classifying this variant as Likely benign (Ambry Genetics, criteria provided), though no expert panel review exists. PS5 and PP5 are not met as the classification is not pathogenic.3 No variant-specific literature, functional studies, de novo observations, or segregation data were identified. Multiple criteria could not be assessed due to absence of evidence. The pathogenic evidence (PM2 supporting) and benign evidence (BP7 supporting_benign) are balanced and of equivalent weight. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules.4
TET2
Final classification
VUS
TET2 c.1413C>T · p.Ser471=
TET2
NM_001127208.2:c.1413C>T (p.Ser471=) is a synonymous variant in TET2 at extremely low population frequency (gnomAD v2.1 AF=0.00142%, 4/282,248 alleles; v4.1 AF=0.00056%, 9/1,614,034 alleles), meeting PM2 at supporting level.
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, BP7 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP7
VUS
TET2 c.1413C>T
PM2 + BP7
→
VUS
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.00142% (4/282,248 alleles), gnomAD v4.1 AF=0.00056% (9/1,614,034 alleles), grpmax FAF=7.04e-06. Absent from gnomAD-Canada. Frequency is well below the 0.1% PM2 threshold for a rare disease variant.
gnomAD v2.1: 4/282248 alleles (AF=1.42e-05)0 homozygotes
✓
BP7
supporting
Benign
This is a synonymous variant (p.Ser471=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00; no donor gain, donor loss, acceptor gain, or acceptor loss). No evidence of cryptic splice site creation. The variant meets BP7 criteria for a silent variant without predicted splice impact.
Synonymous variant: NM_001127208.2:c.1413C>T → NP_001120680.1:p.(Ser471=)SpliceAI max delta = 0.00: no predicted donor gaindonor loss
Assessed · not applied
Pathogenic
PS2
No de novo evidence identified.
PS3
No functional study data available for this variant.
PS4
No case-control or affected-cohort enrichment data available.
PM1
The variant does not lie in a statistically significant mutational hotspot, nor in a critical functional domain where all missense variants are pathogenic.
PM6
No de novo data available.
PP1
No family segregation data available for this variant.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No detailed phenotype data available for individuals carrying this variant.
PP5
PP5 requires a reputable source to have classified the variant as pathogenic.
Benign
BA1
BA1 threshold is >1% allele frequency.
BS1
BS1 threshold is >0.3% allele frequency.
BS2
Variant is present in gnomAD at very low frequency (4 alleles v2.1, 9 alleles v4.1) but the health status of these individuals is unknown.
BS3
No functional studies demonstrating no deleterious effect for this variant.
BS4
No family segregation data available.
BP2
No data on observations of this variant in trans with a pathogenic variant.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact.
BP5
BP5 applies when a variant has not been observed in affected individuals despite being present in a case with an alternate molecular basis.
BP6
BP6 applies when a reputable source reports the variant as benign and the evidence is not available for independent evaluation.
N/A · 8
PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.57609e-06; MAF= 0.00056%, 9/1614034 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20072e-05; MAF= 0.00320%, 2/62486 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.41719e-05; MAF= 0.00142%, 4/282248 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.108e-05; MAF= 0.00311%, 4/128700 alleles, homozygotes = 0); grpmax FAF= 7.04e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00056%
· 9 / 1,614,034
0 hom · FAF 0.00025%
0 hom · FAF 0.00025%
Remaining individuals 2 / 62,486 |
0.0032% |
European (non-Finnish) 7 / 1,180,018 |
0.00059% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0014%
· 4 / 282,248
0 hom · FAF 0.0007%
0 hom · FAF 0.0007%
European (non-Finnish) 4 / 128,700 |
0.0031% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 3806053)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links