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LYFE SCIENCES
Project: HERA
NM_198253.2:c.3184G>A
p.Ala1062Thr  ·  TERT
ACMG/AMP
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Classification rationale
1

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.

clinvar ↗
2

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%.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA1062
Hotspots ↗