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LYFE SCIENCES
Project: HERA
NM_001001890.2:c.569G>A
p.Gly190Glu  ·  RUNX1
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Classification rationale
1

The RUNX1 c.569G>A (p.Gly190Glu) variant has been reported in ClinVar, including an expert-panel assertion of uncertain significance.

clinvar ↗
2

This variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1 (1/250682 alleles; AF 3.98912e-06, 0.00040%), which supports rarity under the RUNX1 PM2_Supporting threshold of 0.00005.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

The altered residue lies within the RUNX1 Runt homology domain residue range 89-204, supporting PM1 at supporting strength, but it is not one of the codons specified for PM1_Strong.

cspec ↗
4

Computational evidence is mixed but does not meet RUNX1 VCEP thresholds for either PP3 or BP4: REVEL is 0.666, BayesDel is 0.313044, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.

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
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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= 3.98912e-06; MAF= 0.00040%, 1/250682 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83174e-06; MAF= 0.00088%, 1/113228 alleles, homozygotes = 0).
gnomAD v4.1Absent from gnomAD v4.1.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 3791471)
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. RUNX1, a transcription factor involved in hematopoietic differentiation, is altered by mutation or chromosomal rearrangement in various hematologic ma
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.666. BayesDel score = 0.313044.
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.
ResidueG190
Hotspots ↗