About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.319_323del, p.(Ala107GlnfsTer2)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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
PVS1Very strong
PVS1 · very strong
This variant is a 5-bp frameshift deletion that causes an early premature stop codon (p.Ala107GlnfsTer2; default RUNX1 transcript consequence p.Ala134fs). RUNX1 loss of function is an established disease mechanism, and the exact ClinGen Myeloid Malignancy VCEP ClinVar record states that this frameshift is predicted to undergo nonsense-mediated decay, supporting PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1. The exact ClinGen Myeloid Malignancy VCEP ClinVar record states that it is completely absent from population databases with at least 20x coverage for RUNX1, meeting RUNX1 PM2_Supporting.
PM5Supporting
PM5 · supporting
The exact ClinGen Myeloid Malignancy VCEP ClinVar record states that this frameshift is downstream of c.98 and applied PM5_Supporting under the RUNX1-specific rule for nonsense or frameshift variants in this region. SpliceAI predicts no significant splice impact (max delta score 0.03), which is below the <=0.20 splice caveat used in the RUNX1 PM5 framework.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: 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.
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 · 3 not met · 9 not assessed · 12 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.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.
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.
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.
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.
No criteria match.
Met · 4
PVS1 Very strongThis variant is a 5-bp frameshift deletion that causes an early premature stop codon (p.Ala107GlnfsTer2; default RUNX1 transcript consequence p.Ala134fs). RUNX1 loss of function is an established disease mechanism, and the exact ClinGen Myeloid Malignancy VCEP ClinVar record states that this frameshift is predicted to undergo nonsense-mediated decay, supporting PVS1 at very strong strength. Details ▾Hide ▴
Rule
Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
Evidence considered
- Frameshift with premature stop: NP_001001890.1:p.(A107Qfs*2) / NM_001754.5:p.Ala134fs
- RUNX1 loss of function established in the active VCEP framework
- ClinVar expert-panel record for this exact genomic variant applied PVS1
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1. The exact ClinGen Myeloid Malignancy VCEP ClinVar record states that it is completely absent from population databases with at least 20x coverage for RUNX1, meeting RUNX1 PM2_Supporting. Details ▾Hide ▴
Rule
PM2_Supporting: minor allele frequency <= 0.00005 with at least 2000 alleles tested and adequate coverage.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- ClinVar expert-panel record explicitly applied PM2_Supporting
Sources
PM5 SupportingThe exact ClinGen Myeloid Malignancy VCEP ClinVar record states that this frameshift is downstream of c.98 and applied PM5_Supporting under the RUNX1-specific rule for nonsense or frameshift variants in this region. SpliceAI predicts no significant splice impact (max delta score 0.03), which is below the <=0.20 splice caveat used in the RUNX1 PM5 framework. Details ▾Hide ▴
Rule
PM5_Supporting is also applied to nonsense/frameshift variants that are downstream of c.98 in RUNX1, with no predicted splice impact.
Evidence considered
- ClinVar expert-panel record explicitly applied PM5_Supporting
- Variant is downstream of c.98 in the default RUNX1 transcript
- SpliceAI max delta score 0.03
Sources
Not met · 3 · evaluated, threshold not reached
PM1 Although this deletion affects the RUNX1 Runt homology region, the retrieved expert-panel ClinVar record for this exact variant applied PVS1, PM2_Supporting, and PM5_Supporting and did not establish PM1 for this frameshift. Available evidence therefore does not support applying PM1 in this pass. Details ▾Hide ▴
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not reach the RUNX1 BA1 threshold of >=0.0015 in any general population dataset. Details ▾Hide ▴
Rule
BA1: minor allele frequency >= 0.0015 in a qualifying general population dataset.
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 fall within the RUNX1 BS1 range of 0.00015 to 0.0015 in a qualifying general population dataset. Details ▾Hide ▴
Rule
BS1: minor allele frequency between 0.00015 and 0.0015 in a qualifying general population dataset.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
Not assessed · 9 · no assessment recorded
PS1 No established alternate nucleotide change producing the same protein consequence was identified from the retrieved evidence, so PS1 was not assessed. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic or likely pathogenic variant regardless of nucleotide change.
Still missing
- Direct review of additional curated RUNX1 variant databases or publications would be needed to establish a same-protein-change precedent
- if one exists.
PS2 No confirmed de novo occurrence with both maternity and paternity established was identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Rule
Confirmed de novo occurrence in a patient meeting RUNX1 phenotypic criteria.
Still missing
- Published family studies or submitter-level evidence documenting confirmed de novo status were not available in the retrieved record set.
PS3 No variant-specific functional study demonstrating abnormal RUNX1 activity for this exact deletion was identified in the retrieved evidence, so PS3 was not assessed. Details ▾Hide ▴
Rule
Validated functional evidence showing abnormal RUNX1 function; not applicable if PVS1 is used per VCEP caveat.
Evidence considered
- OncoKB provided literature leads but no directly reviewed variant-specific functional assay result in the retrieved materials
Still missing
- Direct review of primary functional literature would be needed to determine whether validated variant-specific assay data exist.
Sources
PS4 No exact proband count meeting RUNX1 phenotypic criteria was established from the retrieved evidence, so PS4 was not assessed. Details ▾Hide ▴
Rule
Increased prevalence in affected individuals meeting RUNX1 phenotypic criteria.
Evidence considered
- ClinVar expert-panel record for this variant did not report PS4 use
Still missing
- Primary reports or curated case-level summaries with countable affected probands would be needed to score PS4.
Sources
PM6 No assumed de novo occurrences without full parental confirmation were identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Rule
Assumed de novo occurrence in a patient meeting RUNX1 phenotypic criteria.
Still missing
- Case reports or submitter evidence describing de novo occurrence without complete parentage confirmation were not available in the retrieved evidence.
PP1 No segregation data with countable informative meioses were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
Co-segregation with disease in multiple affected family members with strength based on meiosis count.
Still missing
- Family-level genotype and phenotype data would be needed to count informative meioses.
BS3 No well-established study showing normal function for this exact variant was identified, so BS3 was not assessed. Details ▾Hide ▴
Rule
Well-established functional studies showing no damaging effect on RUNX1 function.
Evidence considered
- OncoKB listed literature leads but no directly reviewed normal-function result for this variant
Still missing
- Direct review of primary functional literature would be needed to determine whether normal-function assay data exist for this exact deletion.
Sources
BS4 No informative nonsegregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
Lack of segregation in >=2 informative meioses.
Still missing
- Family-level data showing phenotype-positive relatives who do not carry the variant would be needed.
BP2 No evidence was identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 was not assessed. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant.
Still missing
- Phase information with another pathogenic variant would be needed.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not applicable in the RUNX1 Myeloid Malignancy VCEP specification. Details ▾Hide ▴
PM4 N/AThis variant is a frameshift deletion. In the RUNX1 VCEP specification, PM4 is used for in-frame insertions or deletions and stop-loss variants, so PM4 is not applicable here. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- RUNX1 PM4 rule is restricted to in-frame indels or stop-loss variants
Sources
PP2 N/APP2 is not applicable in the RUNX1 Myeloid Malignancy VCEP specification. Details ▾Hide ▴
PP3 N/AThis variant is a frameshift deletion rather than a missense, synonymous, or intronic variant in the categories specified for RUNX1 PP3. SpliceAI shows no significant splice effect (max delta score 0.03), so PP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.03
Sources
PP4 N/APP4 is not applicable in the RUNX1 Myeloid Malignancy VCEP specification because the phenotype is not considered sufficiently specific for a single genetic etiology. Details ▾Hide ▴
BS2 N/ABS2 is not applicable in the RUNX1 Myeloid Malignancy VCEP specification because RUNX1-related disease has incomplete penetrance and later onset of hematologic malignancy. Details ▾Hide ▴
BP1 N/ABP1 is not applicable in the RUNX1 Myeloid Malignancy VCEP specification. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the RUNX1 Myeloid Malignancy VCEP specification. Details ▾Hide ▴
BP4 N/AThis variant is a frameshift deletion rather than a missense, synonymous, or intronic variant in the categories specified for RUNX1 BP4. Although SpliceAI is low (max delta score 0.03), BP4 is not applicable for this variant type. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.03
Sources
BP5 N/ABP5 is not applicable in the RUNX1 Myeloid Malignancy VCEP specification. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in the RUNX1 Myeloid Malignancy VCEP specification. Details ▾Hide ▴
BP7 N/AThis variant is a coding frameshift deletion, not a synonymous or intronic variant in the RUNX1 BP7 categories, so BP7 is not applicable. Details ▾Hide ▴
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001001890.2
- Coding (HGVS c.)
- NM_001001890.2:c.319_323del
- Protein (HGVS p.)
- NP_001001890.1:p.(Ala107GlnfsTer2)
- GRCh38
- chr21:34880660 GCCAGC>G
- GRCh37
- chr21:36252957 GCCAGC>G
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/AThis variant is a frameshift deletion rather than a missense, synonymous, or intronic variant in the categories specified for RUNX1 PP3. SpliceAI shows no significant splice effect (max delta score 0.03), so PP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.03
Sources
BP4 N/AThis variant is a frameshift deletion rather than a missense, synonymous, or intronic variant in the categories specified for RUNX1 BP4. Although SpliceAI is low (max delta score 0.03), BP4 is not applicable for this variant type. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.03
Sources
BP7 N/AThis variant is a coding frameshift deletion, not a synonymous or intronic variant in the RUNX1 BP7 categories, so BP7 is not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
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/3663825/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36252957-GCCAGC-G?dataset=…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34880660-GCCAGC-G?datas…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001001890.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/RUNX1/A107Qfs*2
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.319_323del
- 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 Pathogenic (1 clinical laboratory) and as 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 = 0.03).
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.