Starting
Initialising…
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RUNX1
Final classification
Pathogenic
RUNX1 c.319_323del · p.Ala107GlnfsTer2
RUNX1

The RUNX1 c.319_323del (p.Ala107GlnfsTer2; p.A107Qfs*2) variant has been reported in ClinVar and classified as Pathogenic by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.

Gene
RUNX1
Transcript
NM_001001890.2
HGVS · transcript:coding
NM_001001890.2:c.319_323del
Consequence
N/A
GRCh38
chr21:34880660 GCCAGC>G
GRCh37
chr21:36252957 GCCAGC>G
Basis Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PVS1 very strong (+8) + PM2 supporting (+1) + PM5 supporting (+1) + PP5 supporting (+1) = 11 points, which maps to Pathogenic.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PVS1 very strong (+8) + PM2 supporting (+1) + PM5 supporting (+1) + PP5 supporting (+1) = 11 points, which maps to Pathogenic.
Classification rationale
PVS1PM2PM5PP5 Pathogenic
RUNX1 c.319_323del

The RUNX1 c.319_323del (p.Ala107GlnfsTer2; p.A107Qfs*2) variant has been reported in ClinVar and classified as Pathogenic by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 PM2_Supporting threshold of <=0.00005 and far below the BS1 and BA1 population thresholds.2 This 5-bp deletion causes an early frameshift with a premature stop codon, and the exact expert-panel ClinVar record states that the default RUNX1 transcript consequence p.Ala134fs is predicted to undergo nonsense-mediated decay, supporting PVS1; the same record also applied RUNX1-specific PM5_Supporting because the frameshift is downstream of c.98.3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.03), which is below the RUNX1 PP3 threshold of 0.38 and consistent with the <=0.20 splice caveat used for PM5_Supporting.4

PVS1 + PM2 + PM5 + PP5 Pathogenic
Gene diagram · NM_001001890.2 · variants mapped to exon structure
RUNX1 NM_001001890.2
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency · supports pathogenic
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      Absent from gnomAD v4.1.
      v2.1
      Absent from gnomAD v2.1.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v2.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel).
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
      Functional / OncoKB screenshot
      Functional 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 ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots