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LYFE SCIENCES
Project: HERA
NM_001001890.2:c.1332_1334delinsG
p.Leu445GlyfsTer127  ·  RUNX1
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Classification rationale
1

The RUNX1 c.1332_1334delinsG (p.Leu445GlyfsTer127) variant has been reported in ClinVar, including a Likely Pathogenic expert-panel classification by the ClinGen Myeloid Malignancy VCEP.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0 and is below the RUNX1 PM2_Supporting threshold of 0.00005.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

This is a RUNX1 frameshift variant in a gene with an established loss-of-function disease mechanism, supporting use of the RUNX1 PVS1 framework, although the distal position suggests a downgraded rather than full very-strong PVS1 strength.

cspec ↗
4

SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which supports the RUNX1 PM5_Supporting rule for downstream nonsense or frameshift variants and does not support PP3 or BP4 application for this frameshift event.

spliceai ↗ cspec ↗
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
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely Pathogenic by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel).
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 = 0.00).
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.
ResidueL445
Hotspots ↗