About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.444C>T, p.(Thr148=)
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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BP4Supporting
BP4 · supporting
For RUNX1 synonymous variants, BP4 applies when SpliceAI is <= 0.20. This variant has a SpliceAI max delta score of 0.01, which is below that threshold and supports no meaningful predicted splice effect.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely benign.
BP7Supporting
BP7 · supporting
This is a synonymous RUNX1 variant with SpliceAI max delta score 0.01, which is below the BP7 threshold of 0.20, and it does not fall in the excluded near-canonical splice positions specified by the RUNX1 VCEP rule.
Recorded classification: Likely benign
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: BP4 supporting (-1) + BP7 supporting (-1) = -2 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
124 / 1,614,052 alleles
gnomAD v4.1: 124 / 1,614,052 alleles. Recorded AF 7.68253e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.65859e-05; MAF= 0.00566%, 16/282756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.29411e-05; MAF= 0.00929%, 12/129114 alleles, homozygotes = 0); grpmax FAF= 6.015e-05.
No listed criterion applied
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.
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 · 7 not met · 8 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
The RUNX1 c.444C>T (p.Thr148=) variant is reported in ClinVar and is currently classified as Likely Benign by the ClinGen Myeloid Malignancy Variant Curation Expert Panel.
This variant is present in population databases, including gnomAD v4.1 with grpmax FAF 7.574e-05 and gnomAD v2.1 with grpmax FAF 6.015e-05; these values are above the RUNX1 PM2_Supporting threshold of 0.00005 and below the RUNX1 BS1 threshold of 0.00015.
In silico splicing prediction does not support a splice-disrupting effect, with SpliceAI max delta score 0.01, which is below the RUNX1 PP3 threshold of 0.38 and within the BP4 and BP7 benign threshold of 0.20.
No criteria match.
Met · 3
BP4 SupportingFor RUNX1 synonymous variants, BP4 applies when SpliceAI is <= 0.20. This variant has a SpliceAI max delta score of 0.01, which is below that threshold and supports no meaningful predicted splice effect. Details ▾Hide ▴
Rule
RUNX1 VCEP BP4 for synonymous and intronic variants requires SpliceAI <= 0.20.
Evidence considered
- SpliceAI max delta score 0.01.
Sources
BP6 SupportingExpert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely benign. Details ▾Hide ▴
BP7 SupportingThis is a synonymous RUNX1 variant with SpliceAI max delta score 0.01, which is below the BP7 threshold of 0.20, and it does not fall in the excluded near-canonical splice positions specified by the RUNX1 VCEP rule. Details ▾Hide ▴
Rule
RUNX1 VCEP BP7 applies to synonymous variants outside the excluded near-canonical splice positions when SpliceAI <= 0.20.
Evidence considered
- Protein consequence p.(Thr148=).
- SpliceAI max delta score 0.01.
Sources
Not met · 7 · evaluated, threshold not reached
PVS1 RUNX1 loss of function is an established disease mechanism, but this synonymous variant is not a nonsense, frameshift, or canonical +/-1,2 splice variant, and no abnormal RNA evidence was identified to support a loss-of-function effect. Details ▾Hide ▴
Rule
RUNX1 VCEP PVS1 requires the variant to meet the modified RUNX1 loss-of-function/splicing decision framework.
Evidence considered
- RUNX1 PVS1 eligibility is established in the VCEP framework.
- Generic PVS1 scaffold does not place this variant in a default null-variant bucket.
- SpliceAI max delta score is 0.01.
Still missing
- Direct RNA data for this exact variant were not identified.
Sources
PS1 This synonymous variant does not create an amino acid substitution, and no evidence was identified that it causes the same predicted splice effect as an established pathogenic or likely pathogenic RUNX1 variant. Details ▾Hide ▴
Rule
RUNX1 VCEP PS1 applies to the same amino acid change as an established pathogenic/likely pathogenic variant, or for splice variants per SVI splicing recommendations.
Evidence considered
- Protein consequence is p.(Thr148=).
- No qualifying pathogenic or likely pathogenic comparator was identified in the retrieved sources.
Still missing
- No same-splice-event comparator variant was identified.
Sources
PM1 The identified change is synonymous and available evidence does not show that it affects a RUNX1 hotspot or pathogenic missense residue qualifying for PM1. Details ▾Hide ▴
Rule
RUNX1 VCEP PM1 is defined for variants affecting specified amino acid residues within the RHD.
Evidence considered
- Protein consequence is p.(Thr148=).
- No hotspot row was identified for this residue in the retrieved hotspot review.
Sources
PM2 This variant is present in gnomAD v4.1 with grpmax FAF 7.574e-05, which is above the RUNX1 PM2_Supporting threshold of 0.00005; gnomAD v2.1 also shows grpmax FAF 6.015e-05, above that threshold. Details ▾Hide ▴
Rule
RUNX1 VCEP PM2_Supporting requires minor allele frequency <= 0.00005 with sufficient allele count and coverage, using gnomAD v4.1 grpmax FAF when available.
Evidence considered
- gnomAD v4.1 grpmax FAF 7.574e-05.
- gnomAD v2.1 grpmax FAF 6.015e-05.
Sources
PP3 For RUNX1 synonymous variants, PP3 requires SpliceAI >= 0.38. This variant has a SpliceAI max delta score of 0.01, which is below that threshold and does not support a predicted splice-disrupting effect. Details ▾Hide ▴
Rule
RUNX1 VCEP PP3 for synonymous variants requires SpliceAI >= 0.38.
Evidence considered
- SpliceAI max delta score 0.01.
Sources
BA1 This variant does not meet the RUNX1 BA1 threshold. The highest observed population frequency is 8.98323e-05 in gnomAD v4.1 European non-Finnish individuals, which is below the BA1 threshold of 0.0015. Details ▾Hide ▴
Rule
RUNX1 VCEP BA1 requires minor allele frequency >= 0.0015 in a general continental population dataset with >=2000 alleles tested and >=5 observed alleles.
Evidence considered
- gnomAD v4.1 highest subpopulation AF 8.98323e-05.
- BA1 threshold 0.0015.
Sources
BS1 This variant does not meet the RUNX1 BS1 threshold. The highest observed population frequency is 8.98323e-05 in gnomAD v4.1 European non-Finnish individuals, which is below the BS1 lower threshold of 0.00015. Details ▾Hide ▴
Rule
RUNX1 VCEP BS1 requires minor allele frequency between 0.00015 and 0.0015 in a qualifying general continental population dataset with >=2000 alleles tested and >=5 observed alleles.
Evidence considered
- gnomAD v4.1 highest subpopulation AF 8.98323e-05.
- gnomAD v2.1 highest subpopulation AF 9.29411e-05.
- BS1 threshold range begins at 0.00015.
Sources
Not assessed · 8 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant. Details ▾Hide ▴
Rule
RUNX1 VCEP PS2_Supporting requires 1 proven de novo occurrence and PS2_Moderate requires at least 2 proven de novo occurrences in patients with the relevant phenotype.
Evidence considered
- No de novo evidence was retrieved.
Still missing
- Case-level parental testing data were not identified.
Sources
PS3 No published functional or RNA assay data were identified for this exact variant to show an abnormal RUNX1 effect. Details ▾Hide ▴
Rule
RUNX1 VCEP PS3 requires abnormal transactivation and/or qualifying secondary functional assay evidence and is not applied from non-specific oncogenicity context alone.
Evidence considered
- No variant-specific functional evidence was retrieved.
Still missing
- Direct functional or transcript-level assay data were not identified.
Sources
PS4 No proband-level evidence was identified showing this variant in affected individuals at a frequency meeting the RUNX1 case-enrichment thresholds. Details ▾Hide ▴
Rule
RUNX1 VCEP PS4_Supporting requires 1 qualifying proband, PS4_Moderate requires 2-3, and PS4 requires at least 4.
Evidence considered
- ClinVar shows a Likely Benign expert panel classification rather than published pathogenic case enrichment in the retrieved sources.
Still missing
- Independent affected proband counts meeting RUNX1 phenotypic criteria were not identified.
Sources
PM6 No assumed de novo occurrences without full parental confirmation were identified for this variant. Details ▾Hide ▴
PP1 No segregation data were identified showing this variant tracking with RUNX1-related disease in affected family members. Details ▾Hide ▴
BS3 No well-established functional study was identified showing normal RUNX1 activity or normal splicing for this exact variant. Details ▾Hide ▴
Rule
RUNX1 VCEP BS3 requires normal transactivation with or without qualifying secondary assay support depending on strength.
Evidence considered
- No variant-specific benign functional evidence was retrieved.
Still missing
- Direct benign functional or RNA assay data were not identified.
Sources
BS4 No non-segregation data were identified showing this variant in informative relatives who do not track with the RUNX1-related phenotype. Details ▾Hide ▴
BP2 No evidence was identified that this variant is observed in trans with a pathogenic RUNX1 variant or in cis with another pathogenic variant. Details ▾Hide ▴
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not used in the RUNX1 VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion listed as not applicable in the RUNX1 VCEP specification.
Sources
PM4 N/AThis variant is neither an in-frame insertion/deletion nor a stop-loss variant, so PM4 does not apply. Details ▾Hide ▴
Rule
RUNX1 VCEP PM4 applies to qualifying in-frame indels or stop-loss variants.
Evidence considered
- Variant is a synonymous single-nucleotide substitution.
Sources
PM5 N/AThis variant is synonymous rather than missense, so the RUNX1 PM5 missense-residue framework does not apply. Details ▾Hide ▴
Rule
RUNX1 VCEP PM5 is defined for missense variants and selected downstream truncating variants, with additional caveats.
Evidence considered
- Protein consequence is p.(Thr148=).
Sources
PP2 N/APP2 is not used in the RUNX1 VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion listed as not applicable in the RUNX1 VCEP specification.
Sources
PP4 N/APP4 is not applicable in the RUNX1 VCEP framework because the associated phenotype is not considered sufficiently specific for this criterion. Details ▾Hide ▴
Evidence considered
- Criterion listed as not applicable in the RUNX1 VCEP specification.
Sources
PP5 N/APP5 is not used in the RUNX1 VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion listed as not applicable in the RUNX1 VCEP specification.
Sources
BS2 N/ABS2 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion listed as not applicable in the RUNX1 VCEP specification.
Sources
BP1 N/ABP1 is not used in the RUNX1 VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion listed as not applicable in the RUNX1 VCEP specification.
Sources
BP3 N/ABP3 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion listed as not applicable in the RUNX1 VCEP specification.
Sources
BP5 N/ABP5 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
Evidence considered
- Criterion listed as not applicable in the RUNX1 VCEP specification.
Sources
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001754.4
- Coding (HGVS c.)
- NM_001754.4:c.444C>T
- Protein (HGVS p.)
- NP_001745.2:p.(Thr148=)
- GRCh38
- chr21:34880621 G>A
- GRCh37
- chr21:36252918 G>A
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
124 / 1,614,052 alleles
AF 7.68e-05 · 0 homozygotes · FAF 7.57e-05
gnomAD v2.1
16 / 282,756 alleles
AF 5.66e-05 · 0 homozygotes · FAF 6.01e-05
By genetic ancestry
gnomAD v4.1
AF 7.7e-05 · 124 / 1,614,052 alleles · 0 hom · FAF 7.6e-05
| European (non-Finnish)106 / 1,179,976 | 9e-05 |
| Remaining individuals5 / 62,496 | 8e-05 |
| African/African American5 / 75,018 | 6.7e-05 |
| East Asian2 / 44,886 | 4.5e-05 |
| South Asian4 / 91,082 | 4.4e-05 |
| Ashkenazi Jewish1 / 29,608 | 3.4e-05 |
| European (Finnish)1 / 64,016 | 1.6e-05 |
0 alternate alleles recorded in 3 other groups: Admixed American, Amish, Middle Eastern.
gnomAD v2.1
AF 5.7e-05 · 16 / 282,756 alleles · 0 hom · FAF 6e-05
| European (non-Finnish)12 / 129,114 | 9.3e-05 |
| African/African American2 / 24,962 | 8e-05 |
| South Asian2 / 30,614 | 6.5e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 7.68253e-05; MAF= 0.00768%, 124/1614052 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.98323e-05; MAF= 0.00898%, 106/1179976 alleles, homozygotes = 0); grpmax FAF= 7.574e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.65859e-05; MAF= 0.00566%, 16/282756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.29411e-05; MAF= 0.00929%, 12/129114 alleles, homozygotes = 0); grpmax FAF= 6.015e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingFor RUNX1 synonymous variants, BP4 applies when SpliceAI is <= 0.20. This variant has a SpliceAI max delta score of 0.01, which is below that threshold and supports no meaningful predicted splice effect. Details ▾Hide ▴
Rule
RUNX1 VCEP BP4 for synonymous and intronic variants requires SpliceAI <= 0.20.
Evidence considered
- SpliceAI max delta score 0.01.
Sources
BP7 SupportingThis is a synonymous RUNX1 variant with SpliceAI max delta score 0.01, which is below the BP7 threshold of 0.20, and it does not fall in the excluded near-canonical splice positions specified by the RUNX1 VCEP rule. Details ▾Hide ▴
Rule
RUNX1 VCEP BP7 applies to synonymous variants outside the excluded near-canonical splice positions when SpliceAI <= 0.20.
Evidence considered
- Protein consequence p.(Thr148=).
- SpliceAI max delta score 0.01.
Sources
PP3 For RUNX1 synonymous variants, PP3 requires SpliceAI >= 0.38. This variant has a SpliceAI max delta score of 0.01, which is below that threshold and does not support a predicted splice-disrupting effect. Details ▾Hide ▴
Rule
RUNX1 VCEP PP3 for synonymous variants requires SpliceAI >= 0.38.
Evidence considered
- SpliceAI max delta score 0.01.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
124 / 1,614,052 recorded alleles
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/339877/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36252918-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34880621-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001754.4%3Ac.444C…
- OncoKB ↗www.oncokb.org/gene/RUNX1/T148=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107203525
- 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= 7.68253e-05; MAF= 0.00768%, 124/1614052 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.98323e-05; MAF= 0.00898%, 106/1179976 alleles, homozygotes = 0); grpmax FAF= 7.574e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.65859e-05; MAF= 0.00566%, 16/282756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.29411e-05; MAF= 0.00929%, 12/129114 alleles, homozygotes = 0); grpmax FAF= 6.015e-05.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Likely Benign by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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 previously been reported in somatic cancers (COSMIC; COSV55872606, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.