About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.714C>A, p.(Val238=)
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. 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and v4.1 across all populations, meeting the VCEP PM2_Supporting threshold (MAF ≤ 0.00005 with ≥2,000 alleles tested and ≥20x coverage).
PP3Supporting
PP3 · supporting
This synonymous variant has a SpliceAI donor gain delta score of 0.96, which exceeds the VCEP PP3 threshold of ≥0.38 for synonymous variants, indicating creation of a cryptic novel splice donor site. This variant is not at a canonical splice site and no RNA confirmation data is available.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RUNX1 Version 3.1 v3.1 point-based framework: PM2 supporting (+1) + PP3 supporting (+1) = 2 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.960 maximum delta
Recorded SpliceAI maximum delta score: 0.960. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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: 2 met · 14 not met · 0 not assessed · 10 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.714C>A is a synonymous variant (p.Val238=) in exon 7 of RUNX1 that is absent from all population databases (gnomAD v2.1, v4.1).
SpliceAI predicts a strong cryptic splice donor gain (DS_DG=0.96), meeting the VCEP PP3 threshold of ≥0.38 for synonymous variants, suggesting a potential splicing impact.
PM2_Supporting is met: the variant is absent from gnomAD (MAF=0), meeting the VCEP threshold of ≤0.00005.
PVS1 is not met: this is a synonymous variant, not a null variant; predicted splicing effects without RNA confirmation route to PP3 under the RUNX1 VCEP.
PM1 is not met: codon 238 lies outside the Runt homology domain (AA 89-204), the critical functional domain specified by the VCEP.
No functional studies, de novo data, proband counts, co-segregation evidence, or literature reports are available for this variant.
Applying the point-based scoring system (Tavtigian 2020), PM2_Supporting contributes +1 point and PP3 contributes +1 point, for a total of 2 pathogenic points. The variant falls within the 0-5 point range and is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and v4.1 across all populations, meeting the VCEP PM2_Supporting threshold (MAF ≤ 0.00005 with ≥2,000 alleles tested and ≥20x coverage). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0
- MAF = 0
- meeting VCEP PM2_Supporting threshold of ≤ 0.00005
Still missing
- Coverage at the position not explicitly quantified but gnomAD has adequate depth for RUNX1
Sources
PP3 SupportingThis synonymous variant has a SpliceAI donor gain delta score of 0.96, which exceeds the VCEP PP3 threshold of ≥0.38 for synonymous variants, indicating creation of a cryptic novel splice donor site. This variant is not at a canonical splice site and no RNA confirmation data is available. Details ▾Hide ▴
Evidence considered
- SpliceAI DS_DG = 0.96 (donor gain)
- DS_DL = 0.79 (donor loss)
- Meets VCEP PP3 threshold for synonymous variants: SpliceAI ≥ 0.38
- Pangolin score: SG=0.78 (splice gain)
- consistent with cryptic splice site creation
Still missing
- No RNA data to confirm predicted splicing effect
Sources
Not met · 14 · evaluated, threshold not reached
PVS1 NM_001754.4:c.714C>A is a synonymous variant (p.Val238=) and does not fall into the PVS1 null-variant buckets (nonsense, frameshift, or canonical splice consensus). SpliceAI predicts a strong cryptic donor gain (DS_DG=0.96) but the RUNX1 VCEP routes predicted splicing effects to PP3 in the absence of RNA confirmation; PVS1 requires a null variant or RNA-proven splicing effect per the VCEP decision tree. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Val238=)
- not a null variant
- SpliceAI DS_DG=0.96 predicts cryptic donor gain but no RNA confirmation available
- VCEP PVS1 decision tree applies to null variants and RNA-proven splicing effects
Sources
PS2 No de novo occurrence data (with confirmed maternity and paternity) is available for this variant in the FPD/AML phenotype. Details ▾Hide ▴
Evidence considered
- No de novo reports found in any evidence source
Still missing
- No proband or family data available
PS3 No in vitro or in vivo functional studies have been reported for this synonymous variant. No transactivation assay data or secondary functional assay data is available. Details ▾Hide ▴
Evidence considered
- No functional studies identified in the literature or curated databases
Still missing
- No functional data exists for this variant
PS4 This variant has not been reported in any probands meeting RUNX1-phenotypic criteria. It is absent from ClinVar and no patient-level evidence is available. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no proband observations
Still missing
- No proband data available
Sources
PM1 This synonymous variant affects codon 238 (p.Val238=), which lies outside the RUNX1 Runt homology domain (RHD; AA 89-204). The VCEP PM1 rules require the variant to affect a residue within the RHD, with PM1_strong for the 13 hotspot residues and PM1_supporting for other AA 89-204. Details ▾Hide ▴
PM6 No assumed de novo occurrences have been reported for this variant in patients with FPD/AML phenotype. Details ▾Hide ▴
Evidence considered
- No de novo reports in any evidence source
Still missing
- No proband or family data available
PP1 No co-segregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
- No family or meiosis data available
Still missing
- No segregation data available
BA1 This variant is absent from gnomAD. The VCEP BA1 threshold requires MAF ≥ 0.0015 (0.15%) in any general continental population with ≥2,000 alleles and ≥5 variant alleles. MAF = 0 does not meet this threshold. Details ▾Hide ▴
BS1 This variant is absent from gnomAD. The VCEP BS1 threshold requires MAF between 0.00015 (0.015%) and 0.0015 (0.15%) with ≥2,000 alleles and ≥5 variant alleles. MAF = 0 does not meet this threshold. Details ▾Hide ▴
BS3 No functional studies demonstrating normal transactivation (80-115% of wildtype) or normal function in secondary assays are available for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies identified
Still missing
- No functional data available
BS4 No segregation data is available to demonstrate lack of segregation in ≥2 informative meioses. Details ▾Hide ▴
Evidence considered
- No family or meiosis data available
Still missing
- No segregation data available
BP2 No evidence is available that this variant has been observed in trans with a known pathogenic variant or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No phase data available
Still missing
- No trans/cis data available
BP4 The VCEP BP4 rule for synonymous variants requires SpliceAI ≤ 0.20. This variant has SpliceAI DS_DG = 0.96, which does not meet the BP4 threshold. Details ▾Hide ▴
BP7 The VCEP BP7 rule for synonymous variants requires SpliceAI Δ scores ≤ 0.20 and exclusion from the last 3 nucleotides preceding a canonical donor splice site or first nucleotide following a canonical acceptor splice site. While c.714 is not in the terminal exon positions (exon 7 spans c.614-805), the SpliceAI DS_DG score of 0.96 exceeds the 0.20 threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI DS_DG = 0.96
- exceeding BP7 threshold of ≤ 0.20
- Position c.714 is 91 nucleotides upstream of the exon 7 donor site (c.805)
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis variant is synonymous (p.Val238=) and produces no amino acid change; PS1 requires a same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a missense change at an amino acid residue where a different pathogenic missense change has been previously observed. c.714C>A is a synonymous variant (p.Val238=) with no amino acid change; PM5 does not apply. Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPPP2 is not applicable for RUNX1 per VCEP. The missense constraint z-score (2.08 in gnomAD) does not meet the SVI-recommended cutoff of ≥3.09, and nine benign/likely benign missense variants exist in ClinVar. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPPP4 is not applicable for RUNX1 per VCEP. The FPD/AML phenotype is insufficiently specific and can be caused by multiple inherited predisposition syndromes, somatic mutations, or environmental factors. Details ▾Hide ▴
No further detail was recorded.
PP5 VCEPPP5 is not for use per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation for this VCEP. Details ▾Hide ▴
No further detail was recorded.
BS2 VCEPBS2 is not applicable for RUNX1 per VCEP. FPD/AML patients display incomplete penetrance, and the average age of onset of hematologic malignancies is 33 years. Details ▾Hide ▴
No further detail was recorded.
BP1 VCEPBP1 is not applicable for RUNX1 per VCEP, because both truncating and missense variants cause FPD/AML. Details ▾Hide ▴
No further detail was recorded.
BP5 VCEPBP5 is not applicable per VCEP. Patients can carry two pathogenic variants in genes predisposing to hematologic malignancies. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is not for use per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation for this VCEP. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a recognized ACMG/AMP criterion. The standard pathogenic criteria are PVS1, PS1-PS4, PM1-PM6, and PP1-PP5. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001754.4
- Coding (HGVS c.)
- NM_001754.4:c.714C>A
- Protein (HGVS p.)
- NP_001745.2:p.(Val238=)
- GRCh38
- chr21:34834501 G>T
- GRCh37
- chr21:36206798 G>T
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingThis synonymous variant has a SpliceAI donor gain delta score of 0.96, which exceeds the VCEP PP3 threshold of ≥0.38 for synonymous variants, indicating creation of a cryptic novel splice donor site. This variant is not at a canonical splice site and no RNA confirmation data is available. Details ▾Hide ▴
Evidence considered
- SpliceAI DS_DG = 0.96 (donor gain)
- DS_DL = 0.79 (donor loss)
- Meets VCEP PP3 threshold for synonymous variants: SpliceAI ≥ 0.38
- Pangolin score: SG=0.78 (splice gain)
- consistent with cryptic splice site creation
Still missing
- No RNA data to confirm predicted splicing effect
Sources
BP4 The VCEP BP4 rule for synonymous variants requires SpliceAI ≤ 0.20. This variant has SpliceAI DS_DG = 0.96, which does not meet the BP4 threshold. Details ▾Hide ▴
BP7 The VCEP BP7 rule for synonymous variants requires SpliceAI Δ scores ≤ 0.20 and exclusion from the last 3 nucleotides preceding a canonical donor splice site or first nucleotide following a canonical acceptor splice site. While c.714 is not in the terminal exon positions (exon 7 spans c.614-805), the SpliceAI DS_DG score of 0.96 exceeds the 0.20 threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI DS_DG = 0.96
- exceeding BP7 threshold of ≤ 0.20
- Position c.714 is 91 nucleotides upstream of the exon 7 donor site (c.805)
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.96).
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
Recorded maximum delta 0.960
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/?term=NM_001754.4%3Ac.714C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36206798-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34834501-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/21-34834501-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001754.4%3Ac.714C…
- OncoKB ↗www.oncokb.org/gene/RUNX1/V238=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.714C%3EA
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.96).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.