About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.619A>G, p.(Thr207Ala)
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1, with 2/1,612,820 alleles overall and grpmax FAF 2.8e-07. This is below the RUNX1 PM2_Supporting threshold of 0.00005 with more than 2,000 alleles evaluated.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM2 supporting (+1) = 1 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
2 / 1,612,820 alleles
gnomAD v4.1: 2 / 1,612,820 alleles. Recorded AF 1.24006e-06. Recorded homozygote count 0.
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.
No listed criterion applied
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: 1 met · 8 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 NM_001001890.2:c.619A>G (p.(Thr207Ala)) variant has been reported in ClinVar and is currently classified there 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 is present at very low frequency in gnomAD v4.1, with 2/1,612,820 alleles overall and grpmax FAF 2.8e-07, which supports PM2 at supporting strength under the RUNX1 VCEP threshold of 0.00005.
Computational data do not support a splice effect, with SpliceAI max delta score 0.01, and the missense prediction is indeterminate under the RUNX1 VCEP computational rules because REVEL is 0.581, below the PP3 threshold of 0.88 and above the BP4 threshold of 0.50; BayesDel is 0.0617795.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1, with 2/1,612,820 alleles overall and grpmax FAF 2.8e-07. This is below the RUNX1 PM2_Supporting threshold of 0.00005 with more than 2,000 alleles evaluated. Details ▾Hide ▴
Rule
PM2_Supporting: minor allele frequency <= 0.00005 with at least 2000 alleles tested; use grpmax FAF when available in gnomAD v4.1.
Evidence considered
- RUNX1 VCEP PM2 threshold
- gnomAD v2.1
- gnomAD v4.1 grpmax FAF
Sources
Not met · 8 · evaluated, threshold not reached
PVS1 This is a missense substitution, p.(Thr207Ala), and does not fall into the RUNX1 loss-of-function variant categories used for PVS1. Available splicing data also do not support a rescue of PVS1 through an abnormal splice effect, with SpliceAI max delta score 0.01. Details ▾Hide ▴
Rule
Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
Evidence considered
- RUNX1 VCEP PVS1 framework
- gene-level loss-of-function context
- variant-level PVS1 scaffold
- SpliceAI
Sources
PS1 No evidence was identified that this variant causes the same amino acid change as a previously established pathogenic or likely pathogenic RUNX1 variant. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change; or same amino acid change as a likely pathogenic variant at moderate strength.
Evidence considered
- RUNX1 VCEP PS1 rule
- RUNX1 pilot variant reference file
- ClinVar
Still missing
- A direct same-amino-acid pathogenic precedent was not identified in the available RUNX1 VCEP pilot reference material.
Sources
PM1 This missense variant affects Thr207, which is outside the RUNX1 VCEP PM1-defined residues 89-204 in the Runt homology domain, and available hotspot review did not identify a statistically significant hotspot at this residue. Details ▾Hide ▴
Rule
PM1 applies only to specified residues within the RUNX1 Runt homology domain.
Evidence considered
- RUNX1 VCEP PM1 residue rules
- Cancer Hotspots review
Sources
PM5 No evidence was identified for a different pathogenic or likely pathogenic missense change at this same amino acid residue, and SpliceAI does not suggest a splice effect that would alter the interpretation of a missense comparison. Details ▾Hide ▴
Rule
PM5 requires a different pathogenic missense change at the same residue; PM5_Supporting requires a different likely pathogenic missense change at the same residue; PM5 cannot be used if PM1 is applied.
Evidence considered
- RUNX1 VCEP PM5 rule
- SpliceAI
- RUNX1 pilot variant reference file
Still missing
- No same-residue pathogenic precedent was identified in the available RUNX1 VCEP pilot reference material.
Sources
PP3 Computational evidence does not meet the RUNX1 PP3 threshold. REVEL is 0.581, which is below the PP3 threshold of 0.88, and SpliceAI max delta score is 0.01, which is below the PP3 splice threshold of 0.38. Details ▾Hide ▴
Rule
For RUNX1 missense variants, PP3 requires REVEL >= 0.88 or SpliceAI >= 0.38.
Evidence considered
- RUNX1 VCEP PP3 rule
- REVEL 0.581
- SpliceAI 0.01
- BayesDel 0.0617795
Sources
BA1 Population frequency does not meet the RUNX1 BA1 threshold. The observed gnomAD v4.1 frequency is 2/1,612,820 alleles (0.00012%), which is far below the BA1 threshold of 0.15%. Details ▾Hide ▴
Rule
BA1 requires minor allele frequency >= 0.0015 in a general continental population dataset with >=2000 alleles tested and >=5 variant alleles.
Evidence considered
- RUNX1 VCEP BA1 threshold
- gnomAD v4.1
Sources
BS1 Population frequency does not meet the RUNX1 BS1 threshold. The observed gnomAD v4.1 frequency is 2/1,612,820 alleles (0.00012%), which is below the BS1 range of 0.015% to 0.15%. Details ▾Hide ▴
Rule
BS1 requires minor allele frequency between 0.00015 and 0.0015 in a general continental population dataset with >=2000 alleles tested and >=5 variant alleles.
Evidence considered
- RUNX1 VCEP BS1 threshold
- gnomAD v4.1
Sources
BP4 Computational evidence does not meet the RUNX1 BP4 threshold. SpliceAI max delta score is 0.01 and is compatible with no splice effect, but REVEL is 0.581, which is above the BP4 threshold of 0.50. BayesDel is 0.0617795, but the RUNX1 VCEP BP4 rule for missense variants requires both REVEL <0.50 and SpliceAI <=0.20. Details ▾Hide ▴
Rule
For RUNX1 missense variants, BP4 requires REVEL < 0.50 and SpliceAI <= 0.20.
Evidence considered
- RUNX1 VCEP BP4 rule
- SpliceAI 0.01
- REVEL 0.581
- BayesDel 0.0617795
Sources
Not assessed · 8 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity testing was identified for this variant. Details ▾Hide ▴
Rule
PS2_Supporting requires 1 proven de novo occurrence and PS2_Moderate requires at least 2 proven de novo occurrences in patients with RUNX1-associated phenotype.
Evidence considered
- RUNX1 VCEP PS2 rule
- ClinVar
Still missing
- No case-level parental testing data were identified.
Sources
PS3 No published variant-specific functional study was identified showing altered RUNX1 transactivation or abnormal secondary assay results for this variant. Details ▾Hide ▴
Rule
PS3 requires altered transactivation with or without corroborating secondary assay evidence, depending on strength.
Evidence considered
- RUNX1 VCEP PS3 rule
- OncoKB review context
Still missing
- No variant-specific transactivation or secondary functional assay data were identified.
Sources
PS4 This variant is reported in ClinVar, but no proband count meeting RUNX1 phenotypic criteria was identified to support case enrichment under the RUNX1 PS4 rules. Details ▾Hide ▴
Rule
PS4_Supporting requires 1 proband, PS4_Moderate 2-3 probands, and PS4 4 or more probands meeting RUNX1 phenotypic criteria.
Evidence considered
- RUNX1 VCEP PS4 rule
- ClinVar
Still missing
- No published count of affected probands meeting RUNX1 phenotypic criteria was identified.
Sources
PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Rule
PM6_Supporting requires 2-3 assumed de novo occurrences and PM6 requires at least 4 assumed de novo occurrences in patients with RUNX1-associated phenotype.
Evidence considered
- RUNX1 VCEP PM6 rule
- ClinVar
Still missing
- No case-level origin data supporting assumed de novo status were identified.
Sources
PP1 No segregation data were identified for this variant in affected relatives. Details ▾Hide ▴
BS3 No published variant-specific functional study was identified showing normal RUNX1 transactivation or normal secondary assay results for this variant. Details ▾Hide ▴
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Rule
BS4 applies when the variant is observed not to segregate with disease in at least 2 informative meioses.
Evidence considered
- RUNX1 VCEP BS4 rule
Still missing
- No informative meioses showing lack of segregation were identified.
Sources
BP2 No evidence was identified that this variant occurs in trans with a pathogenic RUNX1 variant or in cis with a pathogenic variant. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant.
Evidence considered
- RUNX1 VCEP BP2 rule
Still missing
- No phasing data were identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
PM4 N/AThis is a missense substitution and not an in-frame insertion/deletion or stop-loss variant, so PM4 does not apply. Details ▾Hide ▴
Rule
PM4 applies to in-frame indels in specified regions or stop-loss variants.
Evidence considered
- RUNX1 VCEP PM4 rule
Sources
PP2 N/APP2 is not applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
PP4 N/APP4 is designated not applicable by the RUNX1 VCEP because the RUNX1-associated phenotype is not sufficiently specific for this criterion. Details ▾Hide ▴
PP5 N/APP5 is not used 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 applicable in the RUNX1 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 is limited to synonymous and intronic variants in the RUNX1 VCEP framework and does not apply to this missense variant. Details ▾Hide ▴
Rule
BP7 applies to synonymous or intronic variants with SpliceAI <= 0.20, with RNA-specific extensions when available.
Evidence considered
- RUNX1 VCEP BP7 rule
Sources
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001001890.2
- Coding (HGVS c.)
- NM_001001890.2:c.619A>G
- Protein (HGVS p.)
- NP_001001890.1:p.(Thr207Ala)
- GRCh38
- chr21:34834515 T>C
- GRCh37
- chr21:36206812 T>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
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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
2 / 1,612,820 alleles
AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,612,820 alleles · 0 hom · FAF 2.8e-07
| European (non-Finnish)2 / 1,179,962 | 1.7e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24006e-06; MAF= 0.00012%, 2/1612820 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69497e-06; MAF= 0.00017%, 2/1179962 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Computational evidence does not meet the RUNX1 PP3 threshold. REVEL is 0.581, which is below the PP3 threshold of 0.88, and SpliceAI max delta score is 0.01, which is below the PP3 splice threshold of 0.38. Details ▾Hide ▴
Rule
For RUNX1 missense variants, PP3 requires REVEL >= 0.88 or SpliceAI >= 0.38.
Evidence considered
- RUNX1 VCEP PP3 rule
- REVEL 0.581
- SpliceAI 0.01
- BayesDel 0.0617795
Sources
BP4 Computational evidence does not meet the RUNX1 BP4 threshold. SpliceAI max delta score is 0.01 and is compatible with no splice effect, but REVEL is 0.581, which is above the BP4 threshold of 0.50. BayesDel is 0.0617795, but the RUNX1 VCEP BP4 rule for missense variants requires both REVEL <0.50 and SpliceAI <=0.20. Details ▾Hide ▴
Rule
For RUNX1 missense variants, BP4 requires REVEL < 0.50 and SpliceAI <= 0.20.
Evidence considered
- RUNX1 VCEP BP4 rule
- SpliceAI 0.01
- REVEL 0.581
- BayesDel 0.0617795
Sources
BP7 N/ABP7 is limited to synonymous and intronic variants in the RUNX1 VCEP framework and does not apply to this missense variant. Details ▾Hide ▴
Rule
BP7 applies to synonymous or intronic variants with SpliceAI <= 0.20, with RNA-specific extensions when available.
Evidence considered
- RUNX1 VCEP BP7 rule
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.581. BayesDel score = 0.0617795.
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
2 / 1,612,820 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/3791469/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36206812-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34834515-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001001890.2%3Ac.6…
- OncoKB ↗www.oncokb.org/gene/RUNX1/T207A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.619A%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
This variant is present in gnomAD v4.1 (AF= 1.24006e-06; MAF= 0.00012%, 2/1612820 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69497e-06; MAF= 0.00017%, 2/1179962 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (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 = 0.01). REVEL score = 0.581. BayesDel score = 0.0617795.
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.