NM_198253.2:c.2517G>A (p.Thr839=) is a synonymous variant in TERT exon 9. This variant is common in population databases: gnomAD v2.1 AF 0.268% with 2 homozygotes, grpmax FAF 0.656% (BS1).1 gnomAD v4.1 confirms high frequency: AF 0.233% with 16 homozygotes, grpmax FAF 0.728% (BS1).2 Sixteen homozygotes observed in gnomAD v4.1, incompatible with a highly penetrant telomere biology disorder whether dominant or recessive (BS2).3 Multiple in silico tools predict no functional impact: REVEL 0.176, BayesDel 0.124, SpliceAI max delta 0.00 (BP4).4 Synonymous variant with no predicted splice alteration; SpliceAI max delta 0.00 (BP7).5 ClinVar reports Likely benign (8 laboratories) and Benign (7 laboratories); however, review status is 1-star (criteria provided, single submitter), precluding application of BP6.6 No functional studies, segregation data, case-control evidence, or de novo observations were identified for this variant in any reviewed source.7 Classification: Benign. Two strong benign criteria (BS1, BS2) and two supporting benign criteria (BP4, BP7) are met. No pathogenic criteria are met.8
TERT
Final classification
Benign
TERT c.2517G>A · p.Thr839=
TERT
NM_198253.2:c.2517G>A (p.Thr839=) is a synonymous variant in TERT exon 9.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong, BS2 strong, BP4 supporting benign, BP7 supporting benign; combination = 2 strong benign + 2 supporting benign, which maps to Benign.
Classification rationale
BS1BS2BP4BP7
Benign
TERT c.2517G>A
BS1 + BS2 + BP4 + BP7
→
Benign
4
revelbayesdelspliceai ↗
8
generic_acmg_combination_rules
Gene diagram
· NM_198253.2 · variants mapped to exon structure
TERT
NM_198253.2
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 10 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
This variant is common in the general population. gnomAD v2.1 grpmax FAF is 0.656% (South Asian), and gnomAD v4.1 grpmax FAF is 0.728% (Ashkenazi Jewish). Both far exceed the 0.3% BS1 threshold. Observed in 2 homozygotes in v2.1 and 16 homozygotes in v4.1, confirming this is a common benign polymorphism.
gnomAD v2.1: grpmax FAF 0.656% (>0.3% threshold)gnomAD v4.1: grpmax FAF 0.728% (>0.3% threshold)2 homozygotes (v2.1)
✓
BS2
strong
Benign
Observed in 16 homozygotes in gnomAD v4.1 and 2 homozygotes in gnomAD v2.1. Homozygous occurrence in a general population database is incompatible with a highly penetrant telomere biology disorder whether inherited in a dominant or recessive pattern.
gnomAD v4.1: 16 homozygotes observedgnomAD v2.1: 2 homozygotes observedHomozygous state incompatible with severe dominant or recessive telomere biology disorder
✓
BP4
supporting
Benign
Multiple in silico tools uniformly predict no impact: REVEL score 0.176 (well within benign range), BayesDel score 0.124 (benign range), and SpliceAI max delta 0.00 (no predicted splicing alteration). All computational evidence supports a benign interpretation.
REVEL 0.176 — benign predictionBayesDel 0.124 — benign predictionSpliceAI max delta 0.00 — no splice alteration predicted
✓
BP7
supporting
Benign
NM_198253.2:c.2517G>A is a synonymous variant (p.Thr839=) with SpliceAI max delta score of 0.00, confirming no predicted impact on splicing. The variant does not create or disrupt a canonical splice site. BP7 is met at supporting level.
Synonymous variant p.(Thr839=) with no amino acid changeSpliceAI max delta 0.00 — no splice site creation or disruption predicted
Assessed · not applied
Pathogenic
PS3
No functional studies identified for NM_198253.2:c.2517G>A.
PS4
No case-control data demonstrating enrichment of this variant in affected individuals.
PM1
Synonymous variant.
PM2
This variant is common in population databases.
PP1
No segregation data available for this variant.
PP3
Multiple in silico tools uniformly predict a benign effect: REVEL 0.176, BayesDel 0.124, SpliceAI max delta 0.00.
PP5
ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel.
Benign
BA1
Highest subpopulation allele frequency: 0.735% (South Asian, gnomAD v2.1) and 0.777% (Ashkenazi Jewish, gnomAD v4.1).
BS3
No well-established in vitro or in vivo functional studies demonstrate no damaging effect on protein function or splicing for this specific variant.
BP6
ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel.
N/A · 11
PVS1 · PS1 · PS2 · PM5 · PM6 · PP2 · PP4 · BS4 · BP1 · BP2 · BP5
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00232735; MAF= 0.23274%, 3755/1613422 alleles, homozygotes = 16) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00776817; MAF= 0.77682%, 230/29608 alleles, homozygotes = 3); grpmax FAF= 0.00727701.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00267744; MAF= 0.26774%, 754/281612 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00735006; MAF= 0.73501%, 225/30612 alleles, homozygotes = 1); grpmax FAF= 0.00656256.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0028773072747014113, 53/18420 alleles, homozygotes = 1).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.23%
· 3755 / 1,613,422
16 hom · FAF 0.73%
16 hom · FAF 0.73%
Ashkenazi Jewish 230 / 29,608 |
0.78% 3 hom |
South Asian 706 / 91,084 |
0.78% 8 hom |
Middle Eastern 41 / 6,062 |
0.68% 2 hom |
European (Finnish) 388 / 63,258 |
0.61% |
Remaining individuals 178 / 62,502 |
0.28% 1 hom |
European (non-Finnish) 2154 / 1,180,012 |
0.18% 2 hom |
Admixed American 34 / 60,028 |
0.057% |
African/African American 24 / 75,068 |
0.032% |
+ 2 not observed (Amish, East Asian)
gnomAD v2.1
0.27%
· 754 / 281,612
2 hom · FAF 0.66%
2 hom · FAF 0.66%
South Asian 225 / 30,612 |
0.74% 1 hom |
Ashkenazi Jewish 71 / 10,308 |
0.69% |
European (Finnish) 170 / 25,114 |
0.68% |
European (non-Finnish) 256 / 128,192 |
0.2% 1 hom |
Remaining individuals 12 / 7,206 |
0.17% |
Admixed American 13 / 35,394 |
0.037% |
African/African American 6 / 24,844 |
0.024% |
East Asian 1 / 19,942 |
0.005% |
gnomAD Canada 🇨🇦
0.29%
· 53 / 18,420
1 hom · FAF 0.34%
1 hom · FAF 0.34%
indel · split
Ashkenazi Jewish 10 / 832 |
1.2% 1 hom |
Middle Eastern 1 / 144 |
0.69% |
South Asian 9 / 1,362 |
0.66% |
Remaining individuals 7 / 1,138 |
0.62% |
European (non-Finnish) 24 / 11,740 |
0.2% |
Latino/Admixed American 1 / 838 |
0.12% |
African/African American 1 / 1,020 |
0.098% |
+ 2 not observed (East Asian, European (Finnish))
ClinVar
This variant has been reported in ClinVar as Likely benign (8 clinical laboratories) and as Benign (7 clinical laboratories). (ClinVarID = 263107)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.176. BayesDel score = 0.124075.
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 previously been reported in somatic cancers (COSMIC; COSV104395555, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
22138009 ↗
NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
32171751 ↗
Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR