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LYFE SCIENCES
Project: HERA
NM_001001890.2:c.590G>A
p.Arg197Gln  ·  RUNX1
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Classification rationale
1

The RUNX1 c.590G>A (p.Arg197Gln) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Uncertain Significance, including an expert-panel submission from the ClinGen Myeloid Malignancy VCEP.

clinvar ↗
2

This variant is present at very low frequency in population databases, with gnomAD v4.1 showing 4/1611650 alleles and a grpmax FAF of 6.8e-07, which is below the RUNX1 PM2_Supporting threshold of 5.0e-05.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

No reviewed variant-specific functional evidence demonstrating either abnormal or normal RUNX1 function was identified, so the current evidence does not support PS3 or BS3.

oncokb ↗ cspec ↗
4

This missense change affects Arg197 within the RUNX1 Runt homology domain, supporting PM1_Supporting under the RUNX1 VCEP, but computational evidence does not meet PP3 or BP4 because REVEL is 0.702, SpliceAI is 0.01, and the RUNX1 thresholds are REVEL at least 0.88 for PP3 and less than 0.50 with SpliceAI at most 0.20 for BP4.

cspec ↗ 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
  • —
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= 3.98492e-06; MAF= 0.00040%, 1/250946 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81368e-06; MAF= 0.00088%, 1/113460 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.48193e-06; MAF= 0.00025%, 4/1611650 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23264e-05; MAF= 0.00223%, 1/44790 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 580214)
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 = 0.702. BayesDel score = 0.137586.
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.
ResidueR197
Hotspots ↗