NM_198253.2:c.2775C>T is a synonymous variant (p.His925=) in exon 11 of TERT. SpliceAI predicts no splicing impact (delta score = 0.00).1 This variant is present in gnomAD v4.1 at a global allele frequency of 0.075% (1208/1,613,858 alleles) with 12 homozygotes observed, and is common in the Ashkenazi Jewish subpopulation (~2%).2 ClinVar classifies this variant as Likely benign by 9 clinical laboratories and Benign by 5 clinical laboratories (Variation ID 242230), representing a strong consensus of benign interpretation across 14 independent clinical testing laboratories.3 No publication was found that mentions this specific variant (NM_198253.2:c.2775C>T). The TERT functional study by Yamaguchi et al. (PMID:15814878) examined only nonsynonymous mutations at codons 202, 412, 694, 772, and 1090. The ACMG/AMP guidelines paper (PMID:25741868) does not discuss individual variants. GeneReviews and PDQ summaries (PMIDs:20301408, 20301779, 26389258, 26389333) provide general gene-level overviews without variant-specific data.4 Two supporting benign criteria are met: BP6 (ClinVar consensus of benign classification by multiple clinical laboratories) and BP7 (synonymous variant with no predicted splice impact, and the nucleotide is not conserved as evidenced by high population frequency with multiple homozygotes). Under ACMG/AMP 2015 combination rules, ≥2 supporting benign criteria yields a classification of Likely benign.5
TERT
Final classification
Likely Benign
TERT c.2775C>T · p.His925=
TERT
NM_198253.2:c.2775C>T is a synonymous variant (p.His925=) in exon 11 of TERT. SpliceAI predicts no splicing impact (delta score = 0.00).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP6 supporting benign, BP7 supporting benign; combination = 2 supporting benign, which maps to Likely Benign.
Classification rationale
BP6BP7
Likely Benign
TERT c.2775C>T
BP6 + BP7
→
Likely Benign
5
clinvar ↗spliceai ↗gnomad_v4 ↗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 · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BP6
supporting
Benign
ClinVar reports this variant as Likely benign by 9 clinical laboratories and Benign by 5 clinical laboratories (Variation ID 242230). Fourteen independent clinical laboratory submissions converge on a benign interpretation. Review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel, but the volume and consistency of benign classifications from multiple clinical testing laboratories supports a benign interpretation under generic ACMG.
ClinVar Variation ID 242230: Likely benign (9 labs)Benign (5 labs)14 usable clinical laboratory submissions
✓
BP7
supporting
Benign
Synonymous variant (p.His925=) with SpliceAI predicting no splice impact (max delta score = 0.00). The high population frequency (up to 2% in Ashkenazi Jewish, with 12 homozygotes in gnomAD v4.1) suggests the nucleotide is not highly conserved. A silent variant with no predicted splicing effect and no conservation constraint meets BP7.
SpliceAI max delta = 0.00 — no splice impact predictedp.His925= — synonymousno amino acid change
Assessed · not applied
Pathogenic
PS2
No de novo data available for this variant.
PS3
No functional data exists for this synonymous variant.
PS4
No case-control data or statistically significant enrichment of this variant in affected individuals versus controls.
PM1
This synonymous variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org negative), and position 925 is not within a characterized critical functional domain that a synonymous change would disrupt.
PM2
Global allele frequency in gnomAD v4.1 is 0.075% (1208/1,613,858 alleles), approaching the 0.1% PM2 threshold.
PM6
No de novo observation reported for this variant.
PP1
No segregation data available for this variant.
PP3
SpliceAI predicts no splicing impact (max delta score = 0.00).
PP4
No patient phenotype or family history data available to assess specificity for a TERT-related disorder.
PP5
ClinVar classifies this variant as Likely benign/Benign (Variation ID 242230), not pathogenic.
Benign
BA1
Global allele frequency in gnomAD is below 1% (v2.1: 0.105%, v4.1: 0.075%).
BS1
Global allele frequency in gnomAD is below 0.3% (v2.1: 0.105%, v4.1: 0.075%).
BS2
No specific observation of this variant in healthy adults documented with expected full-penetrance early-age phenotype absent.
BS3
No functional studies have been performed on this variant to demonstrate no damaging effect on protein function or splicing.
BS4
No segregation data available to demonstrate lack of cosegregation with disease.
BP2
No evidence that this variant has been observed in trans with a pathogenic variant in a recessive disorder.
BP4
Insufficient multiple lines of computational evidence.
BP5
No observation of this variant in a case where an alternate molecular basis for disease was identified.
N/A · 5
PVS1 · PS1 · PM5 · PP2 · BP1
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000748517; MAF= 0.07485%, 1208/1613858 alleles, homozygotes = 12) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0191502; MAF= 1.91502%, 567/29608 alleles, homozygotes = 10); grpmax FAF= 0.00426711.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00105174; MAF= 0.10517%, 295/280488 alleles, homozygotes = 5) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0198183; MAF= 1.98183%, 205/10344 alleles, homozygotes = 5); grpmax FAF= 0.00036814.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0018458197611292075, 34/18420 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.075%
· 1208 / 1,613,858
12 hom · FAF 0.43%
12 hom · FAF 0.43%
Ashkenazi Jewish 567 / 29,608 |
1.9% 10 hom |
Middle Eastern 35 / 6,062 |
0.58% |
Remaining individuals 131 / 62,504 |
0.21% 1 hom |
East Asian 78 / 44,876 |
0.17% |
African/African American 40 / 75,052 |
0.053% |
Admixed American 20 / 60,032 |
0.033% |
European (non-Finnish) 321 / 1,180,032 |
0.027% |
South Asian 14 / 91,090 |
0.015% 1 hom |
European (Finnish) 2 / 63,690 |
0.0031% |
+ 1 not observed (Amish)
gnomAD v2.1
0.11%
· 295 / 280,488
5 hom · FAF 0.037%
5 hom · FAF 0.037%
Ashkenazi Jewish 205 / 10,344 |
2% 5 hom |
Remaining individuals 9 / 7,142 |
0.13% |
European (non-Finnish) 56 / 128,346 |
0.044% |
East Asian 8 / 19,530 |
0.041% |
Admixed American 11 / 35,364 |
0.031% |
African/African American 3 / 24,154 |
0.012% |
South Asian 3 / 30,602 |
0.0098% |
+ 1 not observed (European (Finnish))
gnomAD Canada 🇨🇦
0.18%
· 34 / 18,420
0 hom · FAF 0.08%
0 hom · FAF 0.08%
Ashkenazi Jewish 22 / 832 |
2.6% |
Middle Eastern 1 / 144 |
0.69% |
African/African American 3 / 1,020 |
0.29% |
Remaining individuals 3 / 1,136 |
0.26% |
European (non-Finnish) 5 / 11,742 |
0.043% |
+ 4 not observed (Latino/Admixed American, East Asian, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (5 clinical laboratories). (ClinVarID = 242230)
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 previously been reported in somatic cancers (COSMIC; COSV57220253, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
15814878 ↗
Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia.
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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR