About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.1113C>T, p.(Ala371=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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 v3.1.0. 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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0, which is below the RUNX1 PM2_supporting threshold of 0.00005.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
For synonymous RUNX1 variants, BP4 applies when SpliceAI is 0.20 or lower. This variant has a SpliceAI maximum delta score of 0.00, supporting no predicted splice impact.
BP7Supporting
BP7 · supporting
This synonymous variant is not at a canonical splice-site boundary position used to exclude BP7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the RUNX1 BP7 threshold of 0.20.
Recorded classification: Likely benign
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM2 supporting (+1) + BP4 supporting (-1) + BP7 supporting (-1) = -1 points, which maps to Likely 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
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 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
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: 3 met · 5 not met · 8 not assessed · 12 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.1113C>T (p.Ala371=; p.A371=) variant has been reported in ClinVar, where the aggregate record is Uncertain Significance with expert panel review and includes two likely benign laboratory submissions.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing the observed population frequency at 0 and below the RUNX1 PM2_supporting threshold of 0.00005.
SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, which is below the RUNX1 PP3 threshold of 0.38 and at or below the BP4 and BP7 threshold of 0.20 for synonymous variants.
No criteria match.
Met · 3
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0, which is below the RUNX1 PM2_supporting threshold of 0.00005. Details ▾Hide ▴
Rule
PM2_Supporting: minor allele frequency <= 0.00005 with adequate population database representation.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- RUNX1 PM2_supporting threshold <= 0.00005.
Sources
BP4 SupportingFor synonymous RUNX1 variants, BP4 applies when SpliceAI is 0.20 or lower. This variant has a SpliceAI maximum delta score of 0.00, supporting no predicted splice impact. Details ▾Hide ▴
Rule
For synonymous and intronic variants, BP4 applies when SpliceAI is <= 0.20.
Evidence considered
- SpliceAI max delta score 0.00.
- RUNX1 BP4 threshold <= 0.20 for synonymous variants.
Sources
BP7 SupportingThis synonymous variant is not at a canonical splice-site boundary position used to exclude BP7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the RUNX1 BP7 threshold of 0.20. Details ▾Hide ▴
Rule
BP7 applies to eligible synonymous variants and intronic variants with SpliceAI <= 0.20.
Evidence considered
- Protein consequence p.(Ala371=).
- SpliceAI max delta score 0.00.
- RUNX1 BP7 threshold <= 0.20 for eligible synonymous variants.
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 This synonymous variant is not a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no significant splice impact (max delta score 0.00). Available evidence does not support a loss-of-function effect for this variant. Details ▾Hide ▴
Rule
Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
Evidence considered
- RUNX1 has VCEP-supported loss-of-function disease mechanism eligibility.
- Variant-specific PVS1 scaffold does not place this change in a generic null-variant bucket.
- SpliceAI max delta score 0.00.
Sources
PM1 This variant is a synonymous change at Ala371, which is outside the RUNX1 Runt homology domain hotspot region defined for PM1 (residues 89-204). Available evidence does not support location in a critical hotspot or constrained functional residue used for PM1. Details ▾Hide ▴
Rule
PM1_strong applies to 13 specified residues in the RHD; PM1_Supporting applies to other residues 89-204 in the RHD.
Evidence considered
- Protein consequence p.(Ala371=).
- RUNX1 PM1 region is limited to residues 89-204.
- No hotspot evidence identified.
Sources
PP3 For synonymous RUNX1 variants, PP3 requires SpliceAI at least 0.38. This variant has a SpliceAI maximum delta score of 0.00, which is below that threshold and does not support a predicted splice effect. Details ▾Hide ▴
Rule
For synonymous and intronic variants, PP3 applies when SpliceAI is >= 0.38.
Evidence considered
- SpliceAI max delta score 0.00.
- RUNX1 PP3 threshold >= 0.38 for synonymous variants.
Sources
BA1 This variant is absent from gnomAD, so the observed population frequency is 0 and does not reach the RUNX1 BA1 threshold of at least 0.0015. Details ▾Hide ▴
Rule
BA1 applies at minor allele frequency >= 0.0015 in a qualifying population dataset.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- RUNX1 BA1 threshold >= 0.0015.
Sources
BS1 This variant is absent from gnomAD, so the observed population frequency is 0 and does not fall within the RUNX1 BS1 range of 0.00015 to 0.0015. Details ▾Hide ▴
Rule
BS1 applies at minor allele frequency between 0.00015 and 0.0015 in a qualifying population dataset.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- RUNX1 BS1 range 0.00015-0.0015.
Sources
Not assessed · 8 · no assessment recorded
PS2 No proven de novo occurrence with confirmed maternity and paternity was identified for this variant in a patient with a RUNX1-related phenotype. Details ▾Hide ▴
Rule
PS2_Supporting requires 1 proven de novo occurrence; PS2_Moderate requires at least 2 proven de novo occurrences.
Evidence considered
- ClinVar record reviewed.
- No confirmed de novo evidence identified.
Still missing
- Case-level de novo data with parental confirmation were not identified.
Sources
PS3 No published functional study or RNA assay was identified showing an abnormal effect for this exact variant. Details ▾Hide ▴
Rule
Requires abnormal transactivation and/or secondary assay evidence per RUNX1 VCEP specifications.
Evidence considered
- No variant-specific functional evidence identified.
Still missing
- No variant-specific functional or RNA study demonstrating a damaging effect was identified.
Sources
PS4 This variant is present in ClinVar, but no exact proband count meeting RUNX1 phenotypic criteria was identified to support case enrichment. Details ▾Hide ▴
Rule
PS4_Supporting requires 1 proband, PS4_Moderate requires 2-3 probands, and PS4 requires at least 4 probands meeting RUNX1 phenotypic criteria.
Evidence considered
- ClinVar record reviewed.
- No exact PS4-level case count identified.
Still missing
- No phenotype-qualified affected proband count was identified for this exact variant.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant in a patient with a RUNX1-related phenotype. Details ▾Hide ▴
PP1 No segregation data were identified showing that this variant tracks with a RUNX1-related phenotype in informative meioses. Details ▾Hide ▴
BS3 No published RNA study or other functional assay was identified showing normal function for this exact variant. Details ▾Hide ▴
Rule
BS3 requires normal transactivation with or without secondary functional evidence per RUNX1 specifications.
Evidence considered
- No variant-specific benign functional evidence identified.
Still missing
- No variant-specific functional evidence demonstrating normal splicing or normal function was identified.
Sources
BS4 No family data were identified showing that this variant fails to segregate with a RUNX1-related phenotype across informative meioses. Details ▾Hide ▴
BP2 No data were identified showing this variant in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant. Details ▾Hide ▴
Rule
BP2 applies when observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant.
Evidence considered
- ClinVar record reviewed.
- No cis/trans observation identified.
Still missing
- No phase or zygosity evidence relevant to BP2 was identified.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis synonymous variant does not create an altered amino acid, and no evidence was identified that it produces the same pathogenic splicing event as an established pathogenic or likely pathogenic variant. PS1 is not applicable on the current evidence. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic or likely pathogenic variant; for splice variants, follow ClinGen SVI splicing recommendations.
Evidence considered
- Protein consequence p.(Ala371=).
- SpliceAI max delta score 0.00.
Sources
PM3 N/APM3 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
PM4 N/AThis variant is a synonymous single-nucleotide substitution and is not an in-frame insertion/deletion or stop-loss variant, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to qualifying in-frame indels or stop-loss variants.
Evidence considered
- Protein consequence p.(Ala371=).
- No in-frame indel or stop-loss consequence.
Sources
PM5 N/APM5 is intended for missense variants, and this variant is synonymous. No RUNX1-specific PM5 scenario applies on the current evidence. Details ▾Hide ▴
Rule
PM5 applies to qualifying missense variants and selected downstream nonsense/frameshift variants per RUNX1 specifications.
Evidence considered
- Protein consequence p.(Ala371=).
Sources
PP2 N/APP2 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
PP4 N/APP4 is not applicable in the RUNX1 VCEP framework because the RUNX1-associated phenotype is not considered sufficiently specific for this criterion. Details ▾Hide ▴
PP5 N/APP5 is not for use in this VCEP framework. Details ▾Hide ▴
BS2 N/ABS2 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
BP1 N/ABP1 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
BP5 N/ABP5 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not for use in this VCEP framework. Details ▾Hide ▴
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001001890.2
- Coding (HGVS c.)
- NM_001001890.2:c.1113C>T
- Protein (HGVS p.)
- NP_001001890.1:p.(Ala371=)
- GRCh38
- chr21:34792384 G>A
- GRCh37
- chr21:36164681 G>A
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
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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
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 synonymous RUNX1 variants, BP4 applies when SpliceAI is 0.20 or lower. This variant has a SpliceAI maximum delta score of 0.00, supporting no predicted splice impact. Details ▾Hide ▴
Rule
For synonymous and intronic variants, BP4 applies when SpliceAI is <= 0.20.
Evidence considered
- SpliceAI max delta score 0.00.
- RUNX1 BP4 threshold <= 0.20 for synonymous variants.
Sources
BP7 SupportingThis synonymous variant is not at a canonical splice-site boundary position used to exclude BP7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is at or below the RUNX1 BP7 threshold of 0.20. Details ▾Hide ▴
Rule
BP7 applies to eligible synonymous variants and intronic variants with SpliceAI <= 0.20.
Evidence considered
- Protein consequence p.(Ala371=).
- SpliceAI max delta score 0.00.
- RUNX1 BP7 threshold <= 0.20 for eligible synonymous variants.
Sources
PP3 For synonymous RUNX1 variants, PP3 requires SpliceAI at least 0.38. This variant has a SpliceAI maximum delta score of 0.00, which is below that threshold and does not support a predicted splice effect. Details ▾Hide ▴
Rule
For synonymous and intronic variants, PP3 applies when SpliceAI is >= 0.38.
Evidence considered
- SpliceAI max delta score 0.00.
- RUNX1 PP3 threshold >= 0.38 for synonymous variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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/1130934/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36164681-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34792384-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001001890.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/RUNX1/A371=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.1113C%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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) 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).
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.