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LYFE SCIENCES
Project: HERA
NM_001987.4:c.133dup
p.Glu45GlyfsTer21  ·  ETV6
ACMG/AMP
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Classification rationale
1

The ETV6 c.133dup (p.(Glu45GlyfsTer21), p.(E45Gfs*21)) variant has not been reported in ClinVar.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the <0.1% threshold used for PM2_supporting.

gnomad_v2 ↗ gnomad_v4 ↗
3

ETV6 loss of function is supported as a germline disease mechanism, and this variant is an early frameshift predicted to truncate the protein, supporting PVS1 under the generic ClinGen SVI PVS1 framework.

pvs1_generic_framework ↗
4

Published literature curated through OncoKB supports the biological relevance of ETV6 loss of function, but no variant-specific functional assay for c.133dup was identified.

oncokb ↗ PMID:29455655 ↗
5

SpliceAI predicts no significant splice effect for this variant with a maximum delta score of 0.13, and no REVEL or BayesDel score is available for this frameshift variant.

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
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE45
Hotspots ↗