About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.1265A>C, p.(Glu422Ala)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign 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. 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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BA1Stand alone
BA1 · stand alone
The variant has a minor allele frequency ≥ 0.15% in multiple general continental populations with ≥ 2,000 alleles and ≥ 5 variant alleles. gnomAD v4.1 East Asian AF = 0.466% (137/29,388 alleles), Ashkenazi Jewish AF = 0.433% (102/23,548 alleles), European non-Finnish AF = 0.163% (1,509/926,052 alleles). GrpMax FAF = 0.403%. Each exceeds the VCEP BA1 threshold of 0.15%.
BP4Supporting
BP4 · supporting
For missense variants, the VCEP BP4 rule requires REVEL < 0.50 AND SpliceAI ≤ 0.20. This variant has REVEL = 0.052 and SpliceAI max delta = 0.00, both meeting the BP4 thresholds. Multiple lines of computational evidence suggest no deleterious impact.
Recorded classification: Benign
ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RUNX1 Version 3.1 v3.1 point-based framework: BA1 stand-alone benign (-8) + BP4 supporting benign (-1) = -9 points, which maps to Benign.
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
2,207 / 1,264,374 alleles
gnomAD v4.1: 2,207 / 1,264,374 alleles. Recorded AF 0.00174553. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002440214738897023, 2/8196 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance. ClinVar API review status: reviewed by expert panel.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV114455125, n = 1 times).
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, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 15 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001754.4:c.1265A>C (p.Glu422Ala) is a missense variant in RUNX1 exon 9, assessed under the ClinGen Myeloid Malignancy VCEP RUNX1 specification v3.1.
BA1 is met at stand-alone strength: the variant is present in gnomAD v4.1 with an East Asian allele frequency of 0.466% (137/29,388 alleles), Ashkenazi Jewish AF of 0.433% (102/23,548 alleles), and European non-Finnish AF of 0.163% (1,509/926,052 alleles), all exceeding the VCEP BA1 threshold of ≥ 0.15% in a general continental population with ≥ 2,000 alleles and ≥ 5 variant alleles.
BP4 is met at supporting benign strength: REVEL score of 0.052 is below 0.50 and SpliceAI max delta of 0.00 is ≤ 0.20, meeting the VCEP threshold for multiple lines of computational evidence suggesting no impact.
No pathogenic criteria are met. PVS1 is not applicable (missense variant). PM1 is not met (E422 is outside the RHD domain, residues 89-204). PM2 is not met (allele frequency far exceeds the 0.005% threshold). PP3 is not met (REVEL 0.052 << 0.88 threshold). No functional, segregation, de novo, proband, or same-residue pathogenic evidence was identified in the reviewed literature.
Under the Tavtigian point-based classification system adopted by the MM-VCEP, BA1 (stand-alone benign) directs a final classification of Benign regardless of other criteria.
No criteria match.
Met · 2
BA1 Stand aloneThe variant has a minor allele frequency ≥ 0.15% in multiple general continental populations with ≥ 2,000 alleles and ≥ 5 variant alleles. gnomAD v4.1 East Asian AF = 0.466% (137/29,388 alleles), Ashkenazi Jewish AF = 0.433% (102/23,548 alleles), European non-Finnish AF = 0.163% (1,509/926,052 alleles). GrpMax FAF = 0.403%. Each exceeds the VCEP BA1 threshold of 0.15%. Details ▾Hide ▴
Evidence considered
- East Asian AF=0.466%
- 137 alleles in 29
- 388
- Ashkenazi Jewish AF=0.433%
- 102 in 23
- 548
- European non-Finnish AF=0.163%
- 1
- 509 in 926
- 052
- grpmax FAF=0.4026%. All exceed BA1 threshold of 0.15%.
Sources
BP4 SupportingFor missense variants, the VCEP BP4 rule requires REVEL < 0.50 AND SpliceAI ≤ 0.20. This variant has REVEL = 0.052 and SpliceAI max delta = 0.00, both meeting the BP4 thresholds. Multiple lines of computational evidence suggest no deleterious impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.052 (<0.50)
- SpliceAI max delta=0.00 (≤0.20)
- BayesDel=-0.3919 (benign-leaning).
Sources
Not met · 15 · evaluated, threshold not reached
PVS1 NM_001754.4:c.1265A>C is a missense variant (p.Glu422Ala) and does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Not eligible for PVS1 under the RUNX1 PVS1 decision tree. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a null variant.
Sources
pvs1_variant_assessment
PS1 p.Glu422Ala (E422A) has not been previously established as a pathogenic or likely pathogenic variant by the MM-VCEP. No evidence of the same amino acid change classified as P/LP was identified. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Uncertain Significance
- VCEP pilot results do not include this variant.
Sources
clinvar ↗vcep_myeloid_malignancy_vcep_runx1_pilot_results
PS2 No de novo occurrence (proven or assumed) was identified for NM_001754.4:c.1265A>C in any reviewed publication or ClinVar submission. Details ▾Hide ▴
Evidence considered
- No de novo reports in case materials or literature.
Still missing
- No proband data or family studies available.
PS3 No functional studies testing NM_001754.4:c.1265A>C (p.Glu422Ala) or a systematically characterized range including codon 422 were identified. OncoKB reports Unknown Oncogenic Effect for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data in any reviewed publication.
Still missing
- No transactivation assays or secondary functional data available for this variant.
Sources
PS4 No probands meeting RUNX1-phenotypic criteria were identified for this variant in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No proband-level variant-specific data in case materials.
Still missing
- No case reports or cohort studies associating this variant with FPD/AML phenotype.
PM1 The variant p.Glu422Ala lies at codon 422, which is well outside the Runt homology domain (RHD, residues 89-204). PM1 applies only to residues within the RHD per the MM-VCEP specification. Details ▾Hide ▴
Evidence considered
- E422 is outside the RHD domain (89-204)
- not in a recognized hotspot.
Sources
PM2 The VCEP PM2_Supporting threshold requires MAF ≤ 0.00005 (0.005%). This variant has a gnomAD v4.1 overall AF of 0.1746% (0.001746) and grpmax FAF of 0.4026% (0.004026), both far exceeding the PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: overall AF=0.1746%
- grpmax FAF=0.4026% (EAS). Far exceeds PM2_Supporting threshold of 0.005%.
Sources
PM5 No different missense change at codon 422 has been established as pathogenic or likely pathogenic by the MM-VCEP. The ClinVar record for this variant (ID 988848) is classified as Uncertain Significance, and no sister variant at codon 422 was identified in the VCEP pilot results. Details ▾Hide ▴
Evidence considered
- No pathogenic/likely pathogenic missense comparator at codon 422 identified.
Sources
clinvar ↗pm5_candidates
PM6 No assumed de novo occurrences were identified for this variant in any reviewed publication or ClinVar record. Details ▾Hide ▴
Evidence considered
- No de novo reports in case materials.
Still missing
- No de novo data available.
PP1 No co-segregation data (informative meioses) were identified for this variant in any reviewed publication or case material. Details ▾Hide ▴
Evidence considered
- No family or segregation studies available.
Still missing
- No segregation data.
PP3 For missense variants, the VCEP PP3 rule requires REVEL ≥ 0.88 or SpliceAI ≥ 0.38. This variant has REVEL = 0.052 and SpliceAI Δ = 0.00, neither meeting the pathogenic threshold. Details ▾Hide ▴
Evidence considered
- REVEL=0.052 (threshold ≥0.88 not met)
- SpliceAI max delta=0.00
- BayesDel=-0.3919 (benign).
Sources
BS1 BS1 is superseded by BA1, which already applies at a higher (stand-alone) strength. The variant's grpmax FAF of 0.4026% exceeds even the BA1 threshold. Applying both BS1 and BA1 would be double-counting the same population evidence. Details ▾Hide ▴
Evidence considered
- BS1 range (0.015%-0.15%) is exceeded by multiple population frequencies
- BA1 at stand-alone level applies instead.
Sources
BS3 No functional studies demonstrating normal transactivation (80-115% of wild-type) or normal function in secondary assays were identified for p.Glu422Ala. OncoKB reports Unknown Oncogenic Effect. Details ▾Hide ▴
Evidence considered
- No transactivation assay or secondary functional data available showing normal function.
Still missing
- No functional data demonstrating normal activity.
Sources
BS4 No segregation data demonstrating lack of segregation in ≥ 2 informative meioses were identified for this variant. Details ▾Hide ▴
Evidence considered
- No family or segregation studies available.
Still missing
- No segregation data.
BP2 No evidence of this variant observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant was identified. Details ▾Hide ▴
Evidence considered
- No phase data available
- no homozygous observations in gnomAD (homozygotes=0).
Still missing
- No phase or co-occurrence data.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PP2 VCEPNot applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1). Details ▾Hide ▴
PP4 VCEPNot applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1). The FPD/AML phenotype is not specific enough to meet PP4. Details ▾Hide ▴
PP5 VCEPNot for use per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1), following the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BS2 VCEPNot applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1). BS2 is not applicable because FPD/AML patients display incomplete penetrance and the average age of onset of hematologic malignancies is 33 years. Details ▾Hide ▴
BP1 VCEPNot applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1). Details ▾Hide ▴
BP5 VCEPNot applicable per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1). A patient can carry two pathogenic variants in genes predisposing to hematologic malignancies. Details ▾Hide ▴
BP6 VCEPNot for use per the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1), following the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous variants (excluding those near splice sites) and intronic variants with SpliceAI ≤ 0.20. NM_001754.4:c.1265A>C is a missense variant (p.Glu422Ala), not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and intronic variants per VCEP.
Sources
PS5 N/APS5 is not defined in the ClinGen Myeloid Malignancy VCEP RUNX1 specification (v3.1) and is not a standard ACMG/AMP criterion with established rules. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001754.4
- Coding (HGVS c.)
- NM_001754.4:c.1265A>C
- Protein (HGVS p.)
- NP_001745.2:p.(Glu422Ala)
- GRCh38
- chr21:34792313 T>G
- GRCh37
- chr21:36164610 T>G
- ClinVar
- 988848
- COSMIC
- COSV114455125
Gene diagram
Every interpreted variant in RUNX1, mapped onto the exon structure of NM_001754.4. Select a row to find it on the plot.
RUNX1NM_001754.4
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
2,207 / 1,264,374 alleles
AF 0.00175 · 0 homozygotes · FAF 0.00403
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.0017 · 2207 / 1,264,374 alleles · 0 hom · FAF 0.004
| East Asian137 / 29,388 | 0.0047 |
| Ashkenazi Jewish102 / 23,548 | 0.0043 |
| Remaining individuals168 / 47,400 | 0.0035 |
| European (Finnish)126 / 41,164 | 0.0031 |
| European (non-Finnish)1509 / 926,052 | 0.0016 |
| Middle Eastern8 / 4,978 | 0.0016 |
| African/African American90 / 65,062 | 0.0014 |
| Admixed American44 / 46,730 | 0.00094 |
| South Asian23 / 79,184 | 0.00029 |
0 alternate alleles recorded in 1 other group: Amish.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00174553; MAF= 0.17455%, 2207/1264374 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00466177; MAF= 0.46618%, 137/29388 alleles, homozygotes = 0); grpmax FAF= 0.00402616.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002440214738897023, 2/8196 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.052
- BayesDel
- -0.392
How the predictions were used
BP4 SupportingFor missense variants, the VCEP BP4 rule requires REVEL < 0.50 AND SpliceAI ≤ 0.20. This variant has REVEL = 0.052 and SpliceAI max delta = 0.00, both meeting the BP4 thresholds. Multiple lines of computational evidence suggest no deleterious impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.052 (<0.50)
- SpliceAI max delta=0.00 (≤0.20)
- BayesDel=-0.3919 (benign-leaning).
Sources
PP3 For missense variants, the VCEP PP3 rule requires REVEL ≥ 0.88 or SpliceAI ≥ 0.38. This variant has REVEL = 0.052 and SpliceAI Δ = 0.00, neither meeting the pathogenic threshold. Details ▾Hide ▴
Evidence considered
- REVEL=0.052 (threshold ≥0.88 not met)
- SpliceAI max delta=0.00
- BayesDel=-0.3919 (benign).
Sources
BP7 N/ABP7 applies only to synonymous variants (excluding those near splice sites) and intronic variants with SpliceAI ≤ 0.20. NM_001754.4:c.1265A>C is a missense variant (p.Glu422Ala), not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and intronic variants per VCEP.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.052. BayesDel score = -0.391942.
7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 22138009 ↗NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.Febbo PG et al. · 2011NCCN Task Force report on evaluating the clinical utility of tumor markers in oncology. NM_001754.4:c.1265A>C (p.Glu422Ala) was not identified in this paper.Does not name this variant
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP guidelines for sequence variant interpretation. NM_001754.4:c.1265A>C (p.Glu422Ala) was not identified in this paper.Does not name this variant
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PMID 20963938 ↗CEBPA-Associated Familial Acute Myeloid Leukemia (AML).Adam MP et al. · 1993GeneReviews chapter on CEBPA-associated familial AML. NM_001754.4:c.1265A>C (p.Glu422Ala) was not identified in this paper.Does not name this variant
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PMID 23970018 ↗Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Fey MF et al. · 2013ESMO Clinical Practice Guidelines for AML diagnosis, treatment, and follow-up (2013). RUNX1 is mentioned once as a gene of potential prognostic significance. NM_001754.4:c.1265A>C (p.Glu422Ala) was not identified in this paper.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc refinement of ACMG-AMP variant classification criteria. NM_001754.4:c.1265A>C (p.Glu422Ala) was not identified in this paper.Does not name this variant
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PMID 32171751 ↗Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Heuser M et al. · 2020ESMO Clinical Practice Guidelines for AML (2020 update). RUNX1 is mentioned in the context of ELN adverse risk classification and RUNX1-RUNX1T1 fusion. NM_001754.4:c.1265A>C (p.Glu422Ala) was not identified in this paper.Does not name this variant
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PMID 33661592 ↗RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies.Adam MP et al. · 1993GeneReviews chapter on RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies. NM_001754.4:c.1265A>C (p.Glu422Ala) was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2,207 / 1,264,374 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
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/988848/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36164610-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34792313-T-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/21-34792313-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001754.4%3Ac.1265…
- OncoKB ↗www.oncokb.org/gene/RUNX1/E422A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124277702
- 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
This variant is present in gnomAD v4.1 (AF= 0.00174553; MAF= 0.17455%, 2207/1264374 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00466177; MAF= 0.46618%, 137/29388 alleles, homozygotes = 0); grpmax FAF= 0.00402616.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002440214738897023, 2/8196 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 988848)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.052. BayesDel score = -0.391942.
Functional
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
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV114455125, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.