About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.1132C>G, p.(Leu378Val)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 VCEP PM2_Supporting threshold of less than or equal to 0.00005.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
For this missense variant, REVEL is 0.323, which is below the RUNX1 VCEP BP4 cutoff of less than 0.50, and SpliceAI max delta is 0.00, which is at or below the BP4 cutoff of 0.20. BayesDel is also negative at -0.252196, which is directionally consistent with a non-damaging interpretation.
Recorded classification: Uncertain significance
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) = 0 points, which maps to VUS.
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.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
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: 2 met · 7 not met · 8 not assessed · 11 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.1132C>G (p.Leu378Val, p.L378V) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Uncertain Significance, including an expert-panel submission from the ClinGen Myeloid Malignancy Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2_Supporting under the RUNX1 VCEP threshold of less than or equal to 0.00005.
Computational evidence supports a benign effect: REVEL is 0.323, below the RUNX1 BP4 cutoff of less than 0.50, SpliceAI max delta is 0.00, at or below the BP4 cutoff of 0.20, and BayesDel is negative at -0.252196.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RUNX1 VCEP PM2_Supporting threshold of less than or equal to 0.00005. Details ▾Hide ▴
Rule
PM2_Supporting: MAF less than or equal to 0.00005.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- RUNX1 PM2_supporting threshold
Sources
BP4 SupportingFor this missense variant, REVEL is 0.323, which is below the RUNX1 VCEP BP4 cutoff of less than 0.50, and SpliceAI max delta is 0.00, which is at or below the BP4 cutoff of 0.20. BayesDel is also negative at -0.252196, which is directionally consistent with a non-damaging interpretation. Details ▾Hide ▴
Rule
BP4: REVEL less than 0.50 and SpliceAI less than or equal to 0.20 for missense variants.
Evidence considered
- REVEL 0.323
- SpliceAI max delta 0.00
- BayesDel -0.252196
- RUNX1 BP4 rule
Sources
Not met · 7 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, p.(Leu378Val), and does not fall into the RUNX1 loss-of-function categories used for PVS1. Available evidence does not support a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function effect for this variant. Details ▾Hide ▴
Rule
RUNX1 VCEP PVS1 with variant-level assessment showing a non-null missense change.
Evidence considered
- RUNX1 VCEP PVS1 framework
- PVS1 gene gate eligible
- variant-level PVS1 scaffold identifies this as non-null
Sources
PS1 No previously established pathogenic or likely pathogenic RUNX1 variant producing the same amino acid change was identified in the available expert-panel precedent materials or ClinVar, so PS1 is not met. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic or likely pathogenic variant.
Evidence considered
- RUNX1 VCEP PS1 rule
- ClinVar expert-panel VUS entry
- reviewed RUNX1 pilot precedent file
Still missing
- No same-amino-acid pathogenic or likely pathogenic comparator was identified in the reviewed precedent sources.
Sources
PM1 This missense variant affects Leu378, which is outside the RUNX1 Runt homology domain residue range used for PM1 (residues 89-204) and is not one of the specified PM1_strong residues. Available evidence therefore does not support PM1. Details ▾Hide ▴
Rule
PM1 applies only to specified residues within the Runt homology domain.
Evidence considered
- protein consequence p.(Leu378Val)
- RUNX1 PM1 residue-based rule
Sources
PM5 No different pathogenic or likely pathogenic missense change at this amino acid residue was identified in the available expert-panel precedent materials, and SpliceAI does not suggest a splice effect that would change this interpretation. Therefore PM5 is not met from the available evidence. Details ▾Hide ▴
Rule
PM5 requires a different established pathogenic or likely pathogenic missense change at the same residue and no predicted splice effect above threshold.
Evidence considered
- RUNX1 VCEP PM5 rule
- SpliceAI max delta 0.00
- reviewed RUNX1 pilot precedent file
Still missing
- No established pathogenic or likely pathogenic comparator at the same residue was identified in the reviewed precedent sources.
Sources
PP3 REVEL is 0.323, which is below the RUNX1 VCEP PP3 cutoff of 0.88, and SpliceAI max delta is 0.00, which is below the PP3 splice cutoff of 0.38. BayesDel is negative at -0.252196 and does not provide contradictory computational support. Available computational evidence does not support PP3. Details ▾Hide ▴
Rule
PP3 requires REVEL at least 0.88 or SpliceAI at least 0.38 for missense variants.
Evidence considered
- REVEL 0.323
- SpliceAI max delta 0.00
- BayesDel -0.252196
- RUNX1 PP3 rule
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the RUNX1 BA1 threshold of at least 0.0015. Details ▾Hide ▴
Rule
BA1 requires MAF at least 0.0015 in a qualifying population dataset.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- RUNX1 BA1 threshold
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the RUNX1 BS1 frequency range of 0.00015 to 0.0015. Details ▾Hide ▴
Rule
BS1 requires MAF between 0.00015 and 0.0015 in a qualifying population dataset.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- RUNX1 BS1 threshold range
Sources
Not assessed · 8 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PS2_supporting requires 1 proven de novo occurrence; PS2_moderate requires 2 or more.
Evidence considered
- RUNX1 VCEP PS2 thresholds
Still missing
- Confirmed parental testing for one or more affected individuals was not identified.
Sources
PS3 No variant-specific functional study showing altered RUNX1 function was identified, so PS3 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PS3 requires altered transactivation and/or qualifying abnormal secondary assay evidence, depending on strength.
Evidence considered
- RUNX1 VCEP PS3 framework
- OncoKB lacked variant-specific reviewed functional evidence
Still missing
- A validated transactivation assay and/or qualifying secondary abnormal-function assay were not identified.
Sources
PS4 No proband-level evidence was identified showing this variant in one or more individuals meeting RUNX1 phenotypic criteria, so PS4 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PS4_supporting requires 1 qualifying proband; higher strengths require more.
Evidence considered
- RUNX1 VCEP PS4 thresholds
- ClinVar contains an expert-panel VUS entry but no qualifying proband count in the reviewed materials
Still missing
- Case reports or series with qualifying RUNX1 phenotype counts were not identified.
Sources
PM6 No assumed de novo occurrences without full parental confirmation were identified for this variant, so PM6 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PM6_supporting requires 2 to 3 assumed de novo occurrences; PM6 requires 4 or more.
Evidence considered
- RUNX1 VCEP PM6 thresholds
Still missing
- Affected individuals reported as de novo without complete parentage confirmation were not identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PP1 requires 3 or more informative meioses under the RUNX1 VCEP.
Evidence considered
- RUNX1 VCEP PP1 meiosis thresholds
Still missing
- Family-level segregation data with informative meioses were not identified.
Sources
BS3 No well-established functional study showing normal RUNX1 function for this variant was identified, so BS3 cannot be assessed. Details ▾Hide ▴
Rule
BS3 requires normal transactivation, with or without secondary assay support depending on strength.
Evidence considered
- RUNX1 VCEP BS3 framework
- OncoKB lacked variant-specific reviewed functional evidence
Still missing
- A validated transactivation assay and any qualifying secondary normal-function assay were not identified.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
BS4 requires lack of segregation in 2 or more informative meioses.
Evidence considered
- RUNX1 VCEP BS4 threshold
Still missing
- At least 2 informative meioses showing lack of segregation were not identified.
Sources
BP2 No phase data were identified showing this variant in trans with a pathogenic variant or in cis with a pathogenic variant, so BP2 cannot be assessed. Details ▾Hide ▴
Rule
BP2 requires in trans or in cis observation with a pathogenic variant.
Evidence considered
- RUNX1 VCEP BP2 definition
Still missing
- Phase information with a known pathogenic variant was not identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/AThe RUNX1 VCEP does not use PM3. Details ▾Hide ▴
Rule
RUNX1 VCEP marks PM3 as not applicable.
Evidence considered
- RUNX1 VCEP applicability statement for PM3
Sources
PM4 N/APM4 is not applicable because this variant is a missense substitution rather than an in-frame insertion/deletion or stop-loss variant. Details ▾Hide ▴
Rule
PM4 applies to in-frame indels and stop-loss variants.
Evidence considered
- RUNX1 VCEP PM4 definition
Sources
PP2 N/AThe RUNX1 VCEP does not use PP2. Details ▾Hide ▴
Rule
RUNX1 VCEP marks PP2 as not applicable.
Evidence considered
- RUNX1 VCEP applicability statement for PP2
Sources
PP4 N/AThe RUNX1 VCEP specifies that PP4 is not applicable because the FPD/AML phenotype is not sufficiently specific for a single genetic etiology. Details ▾Hide ▴
Rule
RUNX1 VCEP marks PP4 as not applicable.
Evidence considered
- RUNX1 VCEP applicability statement for PP4
Sources
PP5 N/AThe RUNX1 VCEP does not use PP5. Details ▾Hide ▴
Rule
RUNX1 VCEP marks PP5 as not applicable.
Evidence considered
- RUNX1 VCEP applicability statement for PP5
Sources
BS2 N/AThe RUNX1 VCEP does not use BS2. Details ▾Hide ▴
Rule
RUNX1 VCEP marks BS2 as not applicable.
Evidence considered
- RUNX1 VCEP applicability statement for BS2
Sources
BP1 N/AThe RUNX1 VCEP does not use BP1. Details ▾Hide ▴
Rule
RUNX1 VCEP marks BP1 as not applicable.
Evidence considered
- RUNX1 VCEP applicability statement for BP1
Sources
BP3 N/AThe RUNX1 VCEP does not use BP3. Details ▾Hide ▴
Rule
RUNX1 VCEP marks BP3 as not applicable.
Evidence considered
- RUNX1 VCEP applicability statement for BP3
Sources
BP5 N/AThe RUNX1 VCEP does not use BP5. Details ▾Hide ▴
Rule
RUNX1 VCEP marks BP5 as not applicable.
Evidence considered
- RUNX1 VCEP applicability statement for BP5
Sources
BP6 N/AThe RUNX1 VCEP does not use BP6. Details ▾Hide ▴
Rule
RUNX1 VCEP marks BP6 as not applicable.
Evidence considered
- RUNX1 VCEP applicability statement for BP6
Sources
BP7 N/ABP7 is not applicable because this variant is missense rather than synonymous or intronic. Details ▾Hide ▴
Rule
BP7 applies to qualifying synonymous or intronic variants.
Evidence considered
- RUNX1 VCEP BP7 definition
Sources
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001001890.2
- Coding (HGVS c.)
- NM_001001890.2:c.1132C>G
- Protein (HGVS p.)
- NP_001001890.1:p.(Leu378Val)
- GRCh38
- chr21:34792365 G>C
- GRCh37
- chr21:36164662 G>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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in RUNX1
—
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
BP4 SupportingFor this missense variant, REVEL is 0.323, which is below the RUNX1 VCEP BP4 cutoff of less than 0.50, and SpliceAI max delta is 0.00, which is at or below the BP4 cutoff of 0.20. BayesDel is also negative at -0.252196, which is directionally consistent with a non-damaging interpretation. Details ▾Hide ▴
Rule
BP4: REVEL less than 0.50 and SpliceAI less than or equal to 0.20 for missense variants.
Evidence considered
- REVEL 0.323
- SpliceAI max delta 0.00
- BayesDel -0.252196
- RUNX1 BP4 rule
Sources
PP3 REVEL is 0.323, which is below the RUNX1 VCEP PP3 cutoff of 0.88, and SpliceAI max delta is 0.00, which is below the PP3 splice cutoff of 0.38. BayesDel is negative at -0.252196 and does not provide contradictory computational support. Available computational evidence does not support PP3. Details ▾Hide ▴
Rule
PP3 requires REVEL at least 0.88 or SpliceAI at least 0.38 for missense variants.
Evidence considered
- REVEL 0.323
- SpliceAI max delta 0.00
- BayesDel -0.252196
- RUNX1 PP3 rule
Sources
BP7 N/ABP7 is not applicable because this variant is missense rather than synonymous or intronic. Details ▾Hide ▴
Rule
BP7 applies to qualifying synonymous or intronic variants.
Evidence considered
- RUNX1 VCEP BP7 definition
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.323. BayesDel score = -0.252196.
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/3791515/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36164662-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34792365-G-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001001890.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/RUNX1/L378V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.1132C%3EG
- 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 Uncertain Significance 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). REVEL score = 0.323. BayesDel score = -0.252196.
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.