About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.1332_1334delinsG, p.(Leu445GlyfsTer127)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen RUNX1 VCEP v3.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Strong
PVS1 · strong
This variant is a RUNX1 frameshift variant in a gene with an established loss-of-function disease mechanism. Because the frameshift occurs near the 3' end and is predicted to alter the terminal portion of the protein rather than undergo classic nonsense-mediated decay, a downgraded PVS1 strength is appropriate under the RUNX1-specific framework; PVS1_Strong is supported pending manual confirmation of distal-region handling.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0, which is below the RUNX1 PM2_Supporting threshold of 0.00005.
PM5Supporting
PM5 · supporting
Under the RUNX1 specification, PM5_Supporting can be applied to nonsense and frameshift variants downstream of c.98. This variant is a downstream frameshift, SpliceAI predicts no significant splice effect with a max delta score of 0.00, and PM1 does not apply, so PM5_Supporting is met.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PVS1 strong (+4) + PM2 supporting (+1) + PM5 supporting (+1) + PP5 supporting (+1) = 7 points, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen RUNX1 VCEP v3.1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 2 not met · 7 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 4
PVS1 StrongThis variant is a RUNX1 frameshift variant in a gene with an established loss-of-function disease mechanism. Because the frameshift occurs near the 3' end and is predicted to alter the terminal portion of the protein rather than undergo classic nonsense-mediated decay, a downgraded PVS1 strength is appropriate under the RUNX1-specific framework; PVS1_Strong is supported pending manual confirmation of distal-region handling. Details ▾Hide ▴
Rule
RUNX1 VCEP PVS1 decision tree; distal frameshift supports downgraded PVS1 rather than full very strong strength.
Evidence considered
- RUNX1 VCEP includes PVS1 as an applicable criterion
- RUNX1 loss of function is an established disease mechanism
- Variant is a frameshift near the transcript terminus
Still missing
- Manual confirmation of the exact RUNX1 VCEP PVS1 branch for this distal exon 6 frameshift is still needed.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0, which is below the RUNX1 PM2_Supporting threshold of 0.00005. Details ▾Hide ▴
Rule
RUNX1 VCEP PM2_Supporting: MAF <= 0.00005 with sufficient population data.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- RUNX1 PM2_Supporting threshold is <=0.00005
Sources
PM5 SupportingUnder the RUNX1 specification, PM5_Supporting can be applied to nonsense and frameshift variants downstream of c.98. This variant is a downstream frameshift, SpliceAI predicts no significant splice effect with a max delta score of 0.00, and PM1 does not apply, so PM5_Supporting is met. Details ▾Hide ▴
Rule
RUNX1 VCEP PM5_Supporting includes nonsense/frameshift variants downstream of c.98 when splicing is not predicted to be affected and PM1 is not used.
Evidence considered
- Frameshift is downstream of c.98
- SpliceAI max delta score = 0.00
- PM1 not applied
Sources
Not met · 2 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the RUNX1 BA1 threshold of at least 0.0015. Details ▾Hide ▴
Rule
RUNX1 VCEP BA1 requires MAF >= 0.0015.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the RUNX1 BS1 frequency range of 0.00015 to 0.0015. Details ▾Hide ▴
Rule
RUNX1 VCEP BS1 requires frequency within the benign threshold range.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
Not assessed · 7 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
PS4 This variant is reported in ClinVar, including an expert-panel classification, but the available evidence does not provide a verified count of affected probands meeting RUNX1 phenotypic criteria. PS4 therefore cannot be independently applied from the reviewed materials. Details ▾Hide ▴
Rule
RUNX1 VCEP requires at least 1 qualifying proband for PS4_Supporting, 2-3 for PS4_Moderate, or at least 4 for PS4.
Evidence considered
- ClinVar expert-panel submission present
- No independently verified proband count available
Still missing
- No verified affected-proband count meeting RUNX1 PS4 thresholds was identified.
Sources
PM6 No assumed de novo occurrences without full parentage confirmation were identified for this variant, so PM6 cannot be applied from the available evidence. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
RUNX1 VCEP requires at least 3 informative meioses for PP1.
Evidence considered
- No segregation evidence identified
Still missing
- No informative meioses or family segregation data were identified.
Sources
BS3 No directly reviewed functional studies showing normal RUNX1 function for this variant were identified, so BS3 cannot be applied. Details ▾Hide ▴
Rule
RUNX1 VCEP BS3 requires normal transactivation with or without secondary assay support depending on strength.
Evidence considered
- No directly reviewed benign functional evidence identified
Still missing
- No variant-specific normal-function transactivation or secondary assay data were identified.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
RUNX1 VCEP BS4 requires observation in at least 2 informative meioses showing lack of segregation.
Evidence considered
- No non-segregation evidence identified
Still missing
- No informative meioses showing lack of segregation were identified.
Sources
BP2 No evidence was identified that this variant was observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant, so BP2 cannot be applied. Details ▾Hide ▴
Rule
RUNX1 VCEP BP2 requires qualifying cis or trans observations with a pathogenic variant.
Evidence considered
- No phase data identified
Still missing
- No cis/trans phase data were identified.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this is a frameshift variant, not a variant producing the same established amino acid substitution as a previously classified pathogenic or likely pathogenic variant. Details ▾Hide ▴
Rule
RUNX1 VCEP PS1 rule applies to same amino acid substitutions or specified splice-event matches, not to frameshift variants.
Evidence considered
- Variant type is frameshift
Sources
PS3 N/ANo variant-specific functional assay data were identified here, and the RUNX1 specification states that PS3 is not applied when the variant already meets PVS1. Details ▾Hide ▴
Rule
RUNX1 VCEP PS3 is not applicable if the variant meets PVS1.
Evidence considered
- RUNX1 PS3 rule excludes use when PVS1 is met
Still missing
- No directly reviewed variant-specific transactivation or secondary assay data were identified.
Sources
PM1 N/APM1 is not applicable because this variant is not a missense change affecting the RUNX1 runt homology domain hotspot residues defined by the RUNX1 specification. Details ▾Hide ▴
Rule
RUNX1 VCEP PM1 is restricted to specified residues within the runt homology domain.
Evidence considered
- Variant type is frameshift
- Affected residue is outside the RUNX1 PM1-defined hotspot framework
Sources
PM3 N/APM3 is not applicable because the RUNX1 phenotype framework is not evaluated as a recessive disorder in this specification. Details ▾Hide ▴
Rule
RUNX1 VCEP designates PM3 as not applicable.
Evidence considered
- RUNX1 VCEP marks PM3 as not applicable
Sources
PM4 N/APM4 is not applicable because this variant is a frameshift, whereas the RUNX1 PM4 rule is intended for in-frame insertions/deletions in the runt homology domain or for stop-loss variants causing a protein extension. Details ▾Hide ▴
Rule
RUNX1 VCEP PM4 applies to in-frame indels or stop-loss variants, not frameshift variants.
Evidence considered
- Variant type is frameshift
Sources
PP2 N/APP2 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
RUNX1 VCEP designates PP2 as not applicable.
Evidence considered
- RUNX1 VCEP marks PP2 as not applicable
Sources
PP3 N/APP3 is not applicable because this is not a missense, synonymous, or qualifying intronic variant under the RUNX1 computational rule. SpliceAI predicts no significant splice impact, with a max delta score of 0.00. Details ▾Hide ▴
Rule
RUNX1 VCEP PP3 applies to missense, synonymous, or specified intronic variants meeting predictor thresholds.
Evidence considered
- Variant type is frameshift
- SpliceAI max delta score = 0.00
Sources
PP4 N/APP4 is not applicable in the RUNX1 specification because the associated phenotype is not considered sufficiently specific for this rule. Details ▾Hide ▴
Rule
RUNX1 VCEP designates PP4 as not applicable.
Evidence considered
- RUNX1 VCEP marks PP4 as not applicable
Sources
BS2 N/ABS2 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
RUNX1 VCEP designates BS2 as not applicable.
Evidence considered
- RUNX1 VCEP marks BS2 as not applicable
Sources
BP1 N/ABP1 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
RUNX1 VCEP designates BP1 as not applicable.
Evidence considered
- RUNX1 VCEP marks BP1 as not applicable
Sources
BP3 N/ABP3 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
RUNX1 VCEP designates BP3 as not applicable.
Evidence considered
- RUNX1 VCEP marks BP3 as not applicable
Sources
BP4 N/ABP4 is not applicable because this is not a missense, synonymous, or intronic variant within the RUNX1 BP4 computational framework. SpliceAI predicts no significant splice impact, with a max delta score of 0.00, but that alone does not make BP4 applicable to this frameshift variant. Details ▾Hide ▴
Rule
RUNX1 VCEP BP4 applies to missense, synonymous, or intronic variants meeting predictor thresholds.
Evidence considered
- Variant type is frameshift
- SpliceAI max delta score = 0.00
Sources
BP5 N/ABP5 is not applicable in the RUNX1 specification. Details ▾Hide ▴
Rule
RUNX1 VCEP designates BP5 as not applicable.
Evidence considered
- RUNX1 VCEP marks BP5 as not applicable
Sources
BP6 N/ABP6 is not applicable because the RUNX1 VCEP does not use this criterion. Details ▾Hide ▴
Rule
RUNX1 VCEP designates BP6 as not applicable.
Evidence considered
- RUNX1 VCEP marks BP6 as not applicable
Sources
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor intronic under the RUNX1 BP7 rule. Details ▾Hide ▴
Rule
RUNX1 VCEP BP7 applies to synonymous or intronic variants meeting splice-prediction criteria.
Evidence considered
- Variant type is frameshift
Sources
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001001890.2
- Coding (HGVS c.)
- NM_001001890.2:c.1332_1334delinsG
- Protein (HGVS p.)
- NP_001001890.1:p.(Leu445GlyfsTer127)
- GRCh38
- chr21:34792163 AGG>C
- GRCh37
- chr21:36164460 AGG>C
Gene diagram
Every interpreted variant in RUNX1, mapped onto the exon structure of NM_001001890.2. Select a row to find it on the plot.
RUNX1NM_001001890.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in RUNX1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable because this is not a missense, synonymous, or qualifying intronic variant under the RUNX1 computational rule. SpliceAI predicts no significant splice impact, with a max delta score of 0.00. Details ▾Hide ▴
Rule
RUNX1 VCEP PP3 applies to missense, synonymous, or specified intronic variants meeting predictor thresholds.
Evidence considered
- Variant type is frameshift
- SpliceAI max delta score = 0.00
Sources
BP4 N/ABP4 is not applicable because this is not a missense, synonymous, or intronic variant within the RUNX1 BP4 computational framework. SpliceAI predicts no significant splice impact, with a max delta score of 0.00, but that alone does not make BP4 applicable to this frameshift variant. Details ▾Hide ▴
Rule
RUNX1 VCEP BP4 applies to missense, synonymous, or intronic variants meeting predictor thresholds.
Evidence considered
- Variant type is frameshift
- SpliceAI max delta score = 0.00
Sources
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor intronic under the RUNX1 BP7 rule. Details ▾Hide ▴
Rule
RUNX1 VCEP BP7 applies to synonymous or intronic variants meeting splice-prediction criteria.
Evidence considered
- Variant type is frameshift
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637580
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3791500/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36164460-AGG-C?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34792163-AGG-C?dataset=…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001001890.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/RUNX1/L445Gfs*127
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.1332_1334delinsG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.