Classification rationale

BA1BS1BP4 Benign

TERT c.3184G>A

The TERT NM_198253.2:c.3184G>A (p.Ala1062Thr) variant has been reported in ClinVar, where most submissions classify it as benign or likely benign.¹ This variant is common in population databases, with allele frequencies of 1.24601% in gnomAD v2.1 and 1.94967% in gnomAD v4.1, which are above the benign stand-alone threshold of 1.0% and above the BS1 threshold of 0.3%.² In silico prediction does not support a damaging effect, with REVEL 0.207, BayesDel -0.373519, and SpliceAI maximum delta score 0.01 predicting no significant splice impact.³

BA1 + BS1 + BP4 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

Gene diagram · NM_198253.2 · variants mapped to exon structure

TERT NM_198253.2

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.0194967; MAF= 1.94967%, 31441/1612636 alleles, homozygotes = 363) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0242779; MAF= 2.42779%, 28644/1179840 alleles, homozygotes = 340); grpmax FAF= 0.024042.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.0124601; MAF= 1.24601%, 3466/278168 alleles, homozygotes = 44) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0214947; MAF= 2.14947%, 2726/126822 alleles, homozygotes = 40); grpmax FAF= 0.0209994.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

1.9% · 31441 / 1,612,636
363 hom · FAF 2.4%

European (non-Finnish) 28644 / 1,179,840	2.4% 340 hom
Remaining individuals 1097 / 62,482	1.8% 12 hom
Amish 15 / 910	1.6% 1 hom
European (Finnish) 850 / 62,876	1.4% 7 hom
Admixed American 307 / 59,986	0.51%
African/African American 252 / 75,014	0.34% 1 hom
South Asian 211 / 91,052	0.23% 2 hom
Ashkenazi Jewish 59 / 29,578	0.2%
Middle Eastern 3 / 6,044	0.05%
East Asian 3 / 44,854	0.0067%

gnomAD v2.1

1.2% · 3466 / 278,168
44 hom · FAF 2.1%

European (non-Finnish) 2726 / 126,822	2.1% 40 hom
Remaining individuals 103 / 7,090	1.5% 1 hom
European (Finnish) 332 / 24,850	1.3% 1 hom
Admixed American 144 / 35,242	0.41%
African/African American 71 / 23,892	0.3%
Ashkenazi Jewish 25 / 10,256	0.24%
South Asian 64 / 30,562	0.21% 2 hom
East Asian 1 / 19,454	0.0051%

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (10 clinical laboratories) and as Likely benign (6 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely Benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.207. BayesDel score = -0.373519.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TERT is an enzyme that functions to maintain telomere length and genomic stability. The TERT promoter is frequently mutated in various cancer types.

OncoKB ↗

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; COSV57200744, n = 7 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots