About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.1270T>G, p.(Ser424Ala)
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 of 1.05% in the East Asian population (gnomAD v4.1: 255/24222 alleles), exceeding the VCEP BA1 threshold of ≥0.15% in a continental population with ≥2000 alleles and ≥5 variant alleles. This high population frequency is incompatible with a highly penetrant autosomal dominant disorder.
BP4Supporting
BP4 · supporting
REVEL score 0.284 (<0.50) and SpliceAI max delta score 0.00 (≤0.20) meet the VCEP BP4 criteria for missense variants. Multiple in silico predictors (REVEL, BayesDel) indicate a benign computational profile with no predicted splicing 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
3,159 / 1,152,872 alleles
gnomAD v4.1: 3,159 / 1,152,872 alleles. Recorded AF 0.00274011. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0003959611958028113, 4/10102 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
1 reported laboratory submissions
1 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; COSV99038603, 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.1270T>G (p.Ser424Ala) is present in gnomAD v4.1 at an allele frequency of 1.05% in the East Asian population (255/24222 alleles, 0 homozygotes), exceeding the BA1 stand-alone benign threshold of 0.15% for RUNX1.
Multiple in silico predictors support a benign effect: REVEL score 0.284, BayesDel score -0.238, and SpliceAI max delta score 0.00 indicate no predicted impact on protein function or splicing, meeting BP4 at supporting benign strength per RUNX1 VCEP specifications.
The variant is absent from gnomAD v2.1 but is well-represented in gnomAD v4.1 (3159 total alleles), indicating that the larger, more diverse v4.1 dataset captures population variation not visible in earlier releases.
No pathogenic evidence identified: no functional studies, no segregation data, no de novo occurrences, and no probands meeting RUNX1 phenotypic criteria were found in the available literature or databases.
A single somatic occurrence has been reported in COSMIC (COSV99038603, n=1), which is not sufficient to support pathogenicity in the germline context.
ClinVar classification is Uncertain Significance by the ClinGen Myeloid Malignancy VCEP (expert panel reviewed). This assessment incorporates updated gnomAD v4.1 population data not available at the time of that classification.
No criteria match.
Met · 2
BA1 Stand aloneThe variant has a minor allele frequency of 1.05% in the East Asian population (gnomAD v4.1: 255/24222 alleles), exceeding the VCEP BA1 threshold of ≥0.15% in a continental population with ≥2000 alleles and ≥5 variant alleles. This high population frequency is incompatible with a highly penetrant autosomal dominant disorder. Details ▾Hide ▴
Evidence considered
- EAS MAF=1.05276% (255/24222 alleles)
- exceeding BA1 threshold of ≥0.15%
- grpmax FAF=0.95%.
Sources
BP4 SupportingREVEL score 0.284 (<0.50) and SpliceAI max delta score 0.00 (≤0.20) meet the VCEP BP4 criteria for missense variants. Multiple in silico predictors (REVEL, BayesDel) indicate a benign computational profile with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.284 (<0.50)
- SpliceAI max delta=0.00 (≤0.20)
- BayesDel=-0.238 (benign-leaning).
Sources
Not met · 15 · evaluated, threshold not reached
PS1 No prior classification of the same amino acid change (p.Ser424Ala) as pathogenic or likely pathogenic exists. Only one nucleotide change (c.1270T>G) produces S424A, and it is classified as VUS in ClinVar. Details ▾Hide ▴
Evidence considered
- p.Ser424Ala is classified as VUS in ClinVar (variation ID 988867)
- no alternate nucleotide change producing the same amino acid substitution identified.
Sources
clinvar ↗pm5_candidates
PS2 No de novo occurrence data available in the literature or ClinVar. Neither confirmed nor assumed de novo reports were identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observations reported in ClinVar or the literature.
Still missing
- No proband or family data available to assess de novo status.
Sources
PS3 No variant-specific functional data identified. OncoKB reports unknown oncogenic effect with no curated functional PMIDs. No transactivation assay, secondary assay, or systematic range characterization data available for p.Ser424Ala. Details ▾Hide ▴
Evidence considered
- OncoKB classifies as Unknown Oncogenic Effect
- no functional assay data in the literature.
Still missing
- No functional studies of p.Ser424Ala in RUNX1 transactivation assays or other experimental systems.
Sources
PS4 No probands meeting RUNX1-phenotypic criteria (FPD/AML) identified in the available evidence. The variant is present in gnomAD at 0.27% overall frequency, and no case-level data was found in publications or ClinVar submissions beyond general citations to ACMG guidelines. Details ▾Hide ▴
Evidence considered
- ClinVar submissions cite only PMID:25741868 (ACMG guidelines
- not variant-specific case data)
- no proband counts meeting RUNX1 phenotypic criteria available.
Still missing
- No proband-level phenotype data available for this variant.
Sources
PM1 p.Ser424 is located in the C-terminal region of RUNX1, outside the Runt homology domain (RHD, residues 89–204) defined by the VCEP for PM1 application. Not in a VCEP-defined critical functional domain. Details ▾Hide ▴
Evidence considered
- S424 is C-terminal to the RHD
- VCEP PM1 applies to residues 89–204 within the RHD
- with PM1_strong limited to 13 specific DNA-contact residues.
Sources
PM2 gnomAD v4.1 overall allele frequency is 0.274% (3159/1152872 alleles), far exceeding the VCEP PM2_Supporting threshold of ≤0.005% (MAF ≤0.00005). Absent from gnomAD v2.1, but v4.1 data supersedes. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=0.274%
- grpmax FAF=0.95%
- variant is common
- not rare.
Sources
PM5 No other missense variants at codon 424 classified as pathogenic or likely pathogenic identified in ClinVar. No same-residue comparator variants available to support PM5. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue comparator variants
- no P/LP missense changes at codon 424 in ClinVar.
Sources
pm5_candidatesclinvar ↗
PM6 No assumed or confirmed de novo occurrences identified. No reports of this variant arising de novo in patients with FPD/AML phenotype. Details ▾Hide ▴
Evidence considered
- No de novo observations in ClinVar or literature.
Still missing
- No de novo data available.
Sources
PP1 No co-segregation data available. No family studies or meioses counts reported for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data in ClinVar or literature.
Still missing
- No family-based segregation studies available.
PP3 REVEL score 0.284 is below the 0.88 threshold and SpliceAI max delta 0.00 is below the 0.38 threshold required for PP3 under VCEP specifications. Computational predictors do not support a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.284 (<0.88)
- SpliceAI max delta=0.00 (<0.38)
- BayesDel=-0.238 (benign-leaning).
Sources
BS1 The variant allele frequency (EAS 1.05%, overall 0.27%) exceeds the BS1 range of 0.015%–0.15%. The variant qualifies for BA1 (stand-alone benign), which supersedes BS1. Details ▾Hide ▴
BS3 No functional studies demonstrating normal RUNX1 transactivation (80–115% of wild-type) identified. No transactivation assay or secondary assay data available for p.Ser424Ala. Details ▾Hide ▴
Evidence considered
- No functional assay data showing normal transactivation or normal function in a secondary assay.
Still missing
- No functional data available to assess normal vs altered transactivation.
Sources
BS4 No segregation data available to assess lack of segregation in affected families. No informative meioses data reported. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies to evaluate segregation.
BP2 No evidence of this variant occurring in trans with a known pathogenic RUNX1 variant or in a homozygous state in unaffected individuals. Details ▾Hide ▴
Evidence considered
- No trans or cis observations with pathogenic variants reported.
Still missing
- No phase information available for this variant.
PS5 No reputable source reports this variant as pathogenic. ClinVar classification is Uncertain Significance by the ClinGen Myeloid Malignancy VCEP. PS5/PP5 are not applicable under the VCEP specification; assessed under generic ACMG/AMP rules — not met. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Uncertain Significance
- reviewed by expert panel.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Ser424Ala); not a null variant. RUNX1 VCEP PVS1 decision tree applies only to nonsense, frameshift, canonical splice, and initiation codon variants. Details ▾Hide ▴
Evidence considered
- Missense substitution at c.1270
- exon 9
- does not fall into any PVS1 null-variant bucket.
Sources
pvs1_gene_contextpvs1_variant_assessment
PP2 VCEPVCEP specification: PP2 is Not Applicable for RUNX1. Details ▾Hide ▴
Sources
PP4 VCEPVCEP specification: PP4 is Not Applicable for RUNX1. FPD/AML phenotype is not sufficiently specific for a disease with a single genetic etiology. Details ▾Hide ▴
Sources
PP5 VCEPVCEP specification: PP5 is Not Applicable as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
BS2 VCEPVCEP specification: BS2 is Not Applicable for RUNX1. Details ▾Hide ▴
Sources
BP1 VCEPVCEP specification: BP1 is Not Applicable for RUNX1. Details ▾Hide ▴
Sources
BP5 VCEPVCEP specification: BP5 is Not Applicable for RUNX1. Details ▾Hide ▴
Sources
BP6 VCEPVCEP specification: BP6 is Not Applicable as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
BP7 N/ABP7 applies only to synonymous and intronic variants with SpliceAI ≤0.20. This is a missense variant (c.1270T>G, p.Ser424Ala) and is not eligible for BP7. Details ▾Hide ▴
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001754.4
- Coding (HGVS c.)
- NM_001754.4:c.1270T>G
- Protein (HGVS p.)
- NP_001745.2:p.(Ser424Ala)
- GRCh38
- chr21:34792308 A>C
- GRCh37
- chr21:36164605 A>C
- ClinVar
- 988867
- COSMIC
- COSV99038603
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
3,159 / 1,152,872 alleles
AF 0.00274 · 0 homozygotes · FAF 0.00947
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.0027 · 3159 / 1,152,872 alleles · 0 hom · FAF 0.0095
| East Asian255 / 24,222 | 0.011 |
| Ashkenazi Jewish171 / 21,980 | 0.0078 |
| European (Finnish)234 / 38,078 | 0.0061 |
| Remaining individuals247 / 42,882 | 0.0058 |
| Middle Eastern18 / 4,708 | 0.0038 |
| European (non-Finnish)1956 / 833,514 | 0.0023 |
| Admixed American103 / 45,624 | 0.0023 |
| African/African American125 / 63,640 | 0.002 |
| South Asian50 / 77,354 | 0.00065 |
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= 0.00274011; MAF= 0.27401%, 3159/1152872 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0105276; MAF= 1.05276%, 255/24222 alleles, homozygotes = 0); grpmax FAF= 0.00946718.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0003959611958028113, 4/10102 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.284
- BayesDel
- -0.238
How the predictions were used
BP4 SupportingREVEL score 0.284 (<0.50) and SpliceAI max delta score 0.00 (≤0.20) meet the VCEP BP4 criteria for missense variants. Multiple in silico predictors (REVEL, BayesDel) indicate a benign computational profile with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.284 (<0.50)
- SpliceAI max delta=0.00 (≤0.20)
- BayesDel=-0.238 (benign-leaning).
Sources
PP3 REVEL score 0.284 is below the 0.88 threshold and SpliceAI max delta 0.00 is below the 0.38 threshold required for PP3 under VCEP specifications. Computational predictors do not support a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.284 (<0.88)
- SpliceAI max delta=0.00 (<0.38)
- BayesDel=-0.238 (benign-leaning).
Sources
BP7 N/ABP7 applies only to synonymous and intronic variants with SpliceAI ≤0.20. This is a missense variant (c.1270T>G, p.Ser424Ala) and is not eligible for BP7. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.284. BayesDel score = -0.237899.
1 paper record 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
-
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 the interpretation of sequence variants: a joint consensus recommendation of the ACMG and AMP. This is a methodological guideline paper describing the ACMG/AMP variant classification framework. No specific RUNX1 variants are discussed.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3,159 / 1,152,872 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/988867/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36164605-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34792308-A-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/21-34792308-A-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001754.4%3Ac.1270…
- OncoKB ↗www.oncokb.org/gene/RUNX1/S424A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124259850
- 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= 0.00274011; MAF= 0.27401%, 3159/1152872 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0105276; MAF= 1.05276%, 255/24222 alleles, homozygotes = 0); grpmax FAF= 0.00946718.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0003959611958028113, 4/10102 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 988867)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.284. BayesDel score = -0.237899.
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; COSV99038603, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.