About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.1252A>T, p.(Met418Leu)
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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
The variant has a minor allele frequency of 0.50690% (119/23,476 alleles) in the East Asian population in gnomAD v4.1, exceeding the MM-VCEP BA1 threshold of ≥0.15% in a general continental population dataset with ≥2,000 alleles and ≥5 variant alleles. This alone is sufficient to classify the variant as benign.
BP4Supporting
BP4 · supporting
REVEL score is 0.219 (<0.50) and SpliceAI max delta score is 0.00 (≤0.20), meeting the MM-VCEP BP4 threshold for missense variants. Multiple in silico predictors support a benign interpretation.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Benign.
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) + BP6 supporting benign (-1) = -10 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
1,855 / 1,319,142 alleles
gnomAD v4.1: 1,855 / 1,319,142 alleles. Recorded AF 0.00140622. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: reviewed by expert panel.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 3 met · 14 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.1252A>T (p.Met418Leu) in RUNX1 is classified as Benign per the ClinGen Myeloid Malignancy VCEP RUNX1 specifications v3.1.
BA1 is met at stand-alone benign strength: the variant has an allele frequency of 0.507% in the East Asian population (gnomAD v4.1, 119/23,476 alleles, 0 homozygotes), exceeding the MM-VCEP BA1 threshold of ≥0.15% with ≥2,000 alleles tested and ≥5 variant alleles.
BP4 is met at supporting benign strength: REVEL score 0.219 (<0.50) and SpliceAI max delta 0.00 (≤0.20) indicate a benign in silico prediction per MM-VCEP thresholds.
BP6 is met at supporting benign strength: the ClinGen Myeloid Malignancy VCEP expert panel (3-star review) classified this variant as Benign (ClinVar ID 1703790).
The variant is a missense change (p.Met418Leu) in the C-terminal region of RUNX1, outside the Runt homology domain (residues 89–204). No pathogenic criteria are met.
Point-based classification (Tavtigian 2020): BA1 (-8) + BP4 (-1) + BP6 (-1) = −10 points, meeting the Benign threshold (≤−7).
No criteria match.
Met · 3
BA1 Stand aloneThe variant has a minor allele frequency of 0.50690% (119/23,476 alleles) in the East Asian population in gnomAD v4.1, exceeding the MM-VCEP BA1 threshold of ≥0.15% in a general continental population dataset with ≥2,000 alleles and ≥5 variant alleles. This alone is sufficient to classify the variant as benign. Details ▾Hide ▴
Evidence considered
- EAS AF=0.50690% (119/23
- 476 alleles
- 0 homozygotes)
- grpmax FAF=0.004329
- exceeds BA1 ≥0.15% threshold
Sources
BP4 SupportingREVEL score is 0.219 (<0.50) and SpliceAI max delta score is 0.00 (≤0.20), meeting the MM-VCEP BP4 threshold for missense variants. Multiple in silico predictors support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL=0.219 (<0.50)
- SpliceAI max delta=0.00 (≤0.20)
- BayesDel=-0.19 (negative score consistent with benign)
Sources
BP6 SupportingExpert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Benign. Details ▾Hide ▴
Evidence considered
- ClinVar EP (ClinGen MM-VCEP) classification: Benign
- reviewed by expert panel (3-star)
- ClinVar expert panel classification
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No evidence that the same amino acid change (p.Met418Leu) has been previously established as pathogenic or likely pathogenic via a different nucleotide change. Details ▾Hide ▴
PS2 No proven de novo occurrences (with maternity and paternity confirmed) have been reported for this variant in patients with FPD/AML phenotype. Details ▾Hide ▴
PS3 No variant-specific functional data (transactivation assays or secondary functional assays) are available for p.Met418Leu. OncoKB reports unknown oncogenic effect with no curated functional evidence. Details ▾Hide ▴
PS4 No probands meeting RUNX1-phenotypic criteria have been specifically reported for this variant. The variant is present at population frequency in gnomAD, inconsistent with a highly penetrant pathogenic variant. Details ▾Hide ▴
Evidence considered
- No proband data in ClinVar submissions or literature
- variant observed in 1
- 855 alleles in gnomAD v4.1
Sources
PM1 Residue 418 (Met418) lies in the C-terminal region of RUNX1, well outside the Runt homology domain (RHD, residues 89–204) for which the MM-VCEP defines PM1 applicability. PM1_strong is limited to 13 specific RHD residues; PM1_supporting covers residues 89–204. Details ▾Hide ▴
Evidence considered
- Variant at residue 418 is outside RHD (89-204)
- not in cancerhotspots.org significant residues
Sources
PM2 The variant is present in gnomAD v4.1 with a grpmax filtering allele frequency of 0.004329 (0.43%) and an East Asian AF of 0.005069 (0.51%), far exceeding the MM-VCEP PM2_supporting threshold of ≤0.00005 (0.005%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: grpmax FAF=0.004329
- EAS AF=0.005069
- overall AF=0.001406
- all exceed PM2_supporting ≤0.00005 cutoff
Sources
PM5 No different missense changes at residue 418 have been established as pathogenic or likely pathogenic in ClinVar. PM5 requires a different missense change at the same residue with a prior pathogenic/likely pathogenic classification. Details ▾Hide ▴
PM6 No assumed de novo occurrences (without confirmation of maternity and paternity) have been reported for this variant in patients with FPD/AML phenotype. MM-VCEP requires ≥2 assumed de novo for PM6_supporting. Details ▾Hide ▴
PP1 No co-segregation data are available. MM-VCEP requires ≥3 meioses for PP1 at supporting level. Details ▾Hide ▴
PP3 REVEL score is 0.219 (threshold ≥0.88 required) and SpliceAI max delta is 0.00 (threshold ≥0.38 required). Neither in silico predictor meets the MM-VCEP PP3 threshold for missense variants. Details ▾Hide ▴
BS1 BS1 is superseded by BA1. The variant's East Asian AF of 0.50690% exceeds the upper bound of the BS1 range (0.015%–0.15%), meeting the more stringent BA1 stand-alone benign criterion instead. Details ▾Hide ▴
Evidence considered
- EAS AF exceeds BS1 upper bound of 0.15%
- BA1 applies instead
Sources
BS3 No functional data demonstrating normal transactivation activity (80–115% of wild-type) are available for this variant. MM-VCEP BS3 requires transactivation assay data showing normal function. Details ▾Hide ▴
BS4 No non-segregation data are available. MM-VCEP BS4 requires observation in ≥2 informative meioses where the variant does not segregate with disease. Details ▾Hide ▴
BP2 No evidence that this variant has been observed in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant. No homozygous observations have been reported in FPD/AML patients. Details ▾Hide ▴
Evidence considered
- No homozygous observations in gnomAD
- no trans/cis data available
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.1252A>T, p.Met418Leu), not a null variant (nonsense, frameshift, or canonical splice site). PVS1 is applicable only to null variants per the RUNX1 MM-VCEP PVS1 decision tree. Details ▾Hide ▴
Evidence considered
- Missense variant does not fall into any PVS1 null-variant bucket
Sources
PP2 VCEPPP2 (missense in a gene with low rate of benign missense variation) is designated as Not Applicable by the MM-VCEP for RUNX1. Details ▾Hide ▴
PP4 VCEPPP4 (phenotype highly specific for single genetic etiology) is designated as Not Applicable by the MM-VCEP because the FPD/AML phenotype is nonspecific and can be caused by multiple inherited predisposition syndromes. Details ▾Hide ▴
PP5 VCEPPP5 is designated as Not Applicable by the MM-VCEP per ClinGen SVI VCEP Review Committee recommendation. The ClinVar expert panel classification for this variant is Benign, not pathogenic. Details ▾Hide ▴
BS2 VCEPBS2 (observed in healthy adult) is designated as Not Applicable by the MM-VCEP for RUNX1. Details ▾Hide ▴
BP1 VCEPBP1 (missense variant in gene where primarily truncating variants cause disease) is designated as Not Applicable by the MM-VCEP for RUNX1. Details ▾Hide ▴
BP5 VCEPBP5 (variant found in case with alternate molecular basis for disease) is designated as Not Applicable by the MM-VCEP for RUNX1. Details ▾Hide ▴
BP7 N/ABP7 (synonymous or intronic variant with no predicted splice impact) applies only to synonymous and intronic variants per MM-VCEP specification. This is a missense variant (c.1252A>T, p.Met418Leu). Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and intronic variants per MM-VCEP
Sources
PS5 N/APS5 has been subsumed by PP5 in the ACMG/AMP 2015 framework. The MM-VCEP designates PP5 as not applicable for RUNX1, and the ClinVar expert panel classification is Benign (not pathogenic). Details ▾Hide ▴
Evidence considered
- Criterion superseded by PP5 in current framework
- MM-VCEP PP5 flagged as Not Applicable
Sources
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001754.4
- Coding (HGVS c.)
- NM_001754.4:c.1252A>T
- Protein (HGVS p.)
- NP_001745.2:p.(Met418Leu)
- GRCh38
- chr21:34792326 T>A
- GRCh37
- chr21:36164623 T>A
- ClinVar
- 1703790
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
1,855 / 1,319,142 alleles
AF 0.00141 · 0 homozygotes · FAF 0.00433
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.0014 · 1855 / 1,319,142 alleles · 0 hom · FAF 0.0043
| East Asian119 / 23,476 | 0.0051 |
| Ashkenazi Jewish100 / 22,384 | 0.0045 |
| Remaining individuals170 / 47,510 | 0.0036 |
| Middle Eastern9 / 5,000 | 0.0018 |
| African/African American101 / 66,194 | 0.0015 |
| European (non-Finnish)1266 / 987,820 | 0.0013 |
| Admixed American50 / 45,148 | 0.0011 |
| European (Finnish)19 / 39,642 | 0.00048 |
| South Asian21 / 81,118 | 0.00026 |
0 alternate alleles recorded in 1 other group: Amish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00140622; MAF= 0.14062%, 1855/1319142 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00506901; MAF= 0.50690%, 119/23476 alleles, homozygotes = 0); grpmax FAF= 0.00432937.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.219
- BayesDel
- -0.190
How the predictions were used
BP4 SupportingREVEL score is 0.219 (<0.50) and SpliceAI max delta score is 0.00 (≤0.20), meeting the MM-VCEP BP4 threshold for missense variants. Multiple in silico predictors support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL=0.219 (<0.50)
- SpliceAI max delta=0.00 (≤0.20)
- BayesDel=-0.19 (negative score consistent with benign)
Sources
PP3 REVEL score is 0.219 (threshold ≥0.88 required) and SpliceAI max delta is 0.00 (threshold ≥0.38 required). Neither in silico predictor meets the MM-VCEP PP3 threshold for missense variants. Details ▾Hide ▴
BP7 N/ABP7 (synonymous or intronic variant with no predicted splice impact) applies only to synonymous and intronic variants per MM-VCEP specification. This is a missense variant (c.1252A>T, p.Met418Leu). Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and intronic variants per MM-VCEP
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.219. BayesDel score = -0.190388.
2 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 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. · 2015Standards and guidelines for ACMG/AMP sequence variant interpretation. This is the foundational framework paper and does not discuss any specific RUNX1 variants.Does not name this variant
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PMID 33661592 ↗RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies.Adam MP et al. · 1993GeneReviews clinical summary of RUNX1 familial platelet disorder with associated myeloid malignancies (FPD/AML). This is a gene-level review and does not mention the specific variant NM_001754.4:c.1252A>T.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1,855 / 1,319,142 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
1 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/1703790/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36164623-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34792326-T-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/21-34792326-T-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001754.4%3Ac.1252…
- OncoKB ↗www.oncokb.org/gene/RUNX1/M418L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.1252A%3ET
- 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= 0.00140622; MAF= 0.14062%, 1855/1319142 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00506901; MAF= 0.50690%, 119/23476 alleles, homozygotes = 0); grpmax FAF= 0.00432937.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 1703790)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.219. BayesDel score = -0.190388.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.