About RUNX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RUNX1 c.30C>T, p.(Ser10=)
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: 3
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
The variant is extremely rare in population databases. In gnomAD v4.1, the minor allele frequency is 6.26e-7 (0.00006%) with 1 allele observed across 1,598,264 alleles, well below the VCEP PM2_Supporting threshold of ≤0.00005. GrpMax FAF is unavailable; all subpopulations satisfy the PM2_Supporting threshold. The variant is absent from gnomAD v2.1.
Benign criteria applied · 3
BP4Supporting
BP4 · supporting
For synonymous variants, the RUNX1 VCEP applies BP4 when SpliceAI ≤ 0.20. SpliceAI max delta score for c.30C>T is 0.03, well below the 0.20 threshold, predicting no impact on splicing. REVEL is not applicable for this synonymous variant.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely benign.
BP7Supporting
BP7 · supporting
c.30C>T is a synonymous variant in exon 1 at CDS position 30, located 240 nucleotides upstream of the exon 1 donor splice site (c.270). It is not within the last 3 nucleotides preceding a canonical donor or the first nucleotide following a canonical acceptor. SpliceAI max delta is 0.03, well below the VCEP BP7 threshold of ≤0.20. The variant meets all BP7 criteria under the RUNX1 VCEP.
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
1 / 1,598,264 alleles
gnomAD v4.1: 1 / 1,598,264 alleles. Recorded AF 6.25679e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Likely benign.
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 v3.1.0, with the data and sources behind each one.
29 criteria with recorded statuses: 4 met · 12 not met · 0 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001001890.2:c.30C>T (p.Ser10=) is a synonymous variant in exon 1 of RUNX1. SpliceAI predicts no significant splicing impact (max delta 0.03), supporting BP4 and BP7 at the supporting benign level per the RUNX1 MM-VCEP v3.1.0.
In gnomAD v4.1, c.30C>T is observed at an extremely low frequency (1/1,598,264 alleles; AF=6.26e-7), well below the VCEP PM2_Supporting threshold of ≤0.00005. All subpopulations satisfy the threshold, and the variant is absent from gnomAD v2.1.
ClinVar reports c.30C>T as Likely Benign, with expert panel review status from the ClinGen Myeloid Malignancy Variant Curation Expert Panel. No contradictory evidence supporting pathogenicity was identified in verified publications.
No functional studies, de novo occurrences, proband case data, or segregation evidence for c.30C>T were identified in any verified publication. All ClinVar-linked PMIDs are about unrelated topics (newborn screening policy statements) and do not mention RUNX1 or this variant.
Applying the RUNX1 MM-VCEP v3.1.0 point-based classification framework (Tavtigian et al. 2020): PM2_Supporting (+1), BP4 (-1), BP7 (-1). Total score: -1. This falls in the Likely Benign range (-6 to -1).
No criteria match.
Met · 4
PM2 SupportingThe variant is extremely rare in population databases. In gnomAD v4.1, the minor allele frequency is 6.26e-7 (0.00006%) with 1 allele observed across 1,598,264 alleles, well below the VCEP PM2_Supporting threshold of ≤0.00005. GrpMax FAF is unavailable; all subpopulations satisfy the PM2_Supporting threshold. The variant is absent from gnomAD v2.1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=6.26e-7 (1/1
- 598
- 264 alleles
- 0 homozygotes)
- gnomAD v4.1 NFE subpopulation: AF=8.48e-7 (1/1
- 179
- 858)
- Allele frequency well below VCEP PM2_Supporting threshold of 0.00005
- gnomAD v2.1: absent
Sources
BP4 SupportingFor synonymous variants, the RUNX1 VCEP applies BP4 when SpliceAI ≤ 0.20. SpliceAI max delta score for c.30C>T is 0.03, well below the 0.20 threshold, predicting no impact on splicing. REVEL is not applicable for this synonymous variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.03 (well below BP4 threshold of 0.20)
- No predicted splice-altering effect
Sources
BP6 SupportingExpert panel ClinGen Myeloid Malignancy Variant Curation Expert Panel classified as Likely benign. Details ▾Hide ▴
BP7 Supportingc.30C>T is a synonymous variant in exon 1 at CDS position 30, located 240 nucleotides upstream of the exon 1 donor splice site (c.270). It is not within the last 3 nucleotides preceding a canonical donor or the first nucleotide following a canonical acceptor. SpliceAI max delta is 0.03, well below the VCEP BP7 threshold of ≤0.20. The variant meets all BP7 criteria under the RUNX1 VCEP. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Ser10=) not in exonic splice consensus region
- SpliceAI max delta = 0.03 (≤0.20 threshold)
- Located at c.30
- far from exon 1 donor site at c.270
Sources
Not met · 12 · evaluated, threshold not reached
PS2 No proven de novo occurrence of c.30C>T (with both maternity and paternity confirmed) in a patient with FPD/AML phenotype has been identified in any verified publication. Details ▾Hide ▴
Evidence considered
- No de novo reports found in reviewed literature
Still missing
- No published de novo occurrences identified
Sources
2361927523652378256267072573023023169492
PS3 No functional assay (transactivation, minigene splicing, or secondary assay) specifically assessing c.30C>T has been identified. Computational predictions (SpliceAI max delta 0.03) are not sufficient to meet PS3. Details ▾Hide ▴
Evidence considered
- No functional studies identified
- SpliceAI predicts no significant splice impact (max delta 0.03)
Still missing
- No functional assay data available for this variant
Sources
PS4 No probands meeting RUNX1-phenotypic criteria have been identified in any verified publication specifically reporting c.30C>T. All ClinVar-linked publications are about unrelated topics (newborn screening policy statements) and do not mention RUNX1 or this variant. Details ▾Hide ▴
Evidence considered
- No verified proband observations with FPD/AML phenotype
Still missing
- No case-level proband data with phenotypic criteria available
Sources
236192752365237825626707257302302316949222947299230379332388147324022298241211472439468028492532
PM1 c.30C>T is at codon 10 in the N-terminal region, outside the Runt homology domain (aa 50-177) and outside the VCEP-defined functionally critical residues (aa 89-204 in the RHD). No mutational hotspot has been established at this position. Details ▾Hide ▴
Evidence considered
- Variant located at codon 10
- outside the RHD critical region (aa 89-204)
- not a recognized mutational hotspot
Sources
PM6 No assumed de novo occurrences of c.30C>T (without confirmation of maternity and paternity) in patients with FPD/AML phenotype have been identified in any verified publication. Details ▾Hide ▴
Evidence considered
- No assumed de novo reports found in reviewed literature
Still missing
- No published assumed de novo observations identified
Sources
2361927523652378256267072573023023169492
PP1 No co-segregation data (meioses observed within families with FPD/AML) has been identified for c.30C>T in any verified publication. Details ▾Hide ▴
Evidence considered
- No segregation data identified in reviewed literature
Still missing
- No segregation or family study data available
Sources
2361927523652378256267072573023023169492
PP3 For synonymous variants, the RUNX1 VCEP requires SpliceAI ≥ 0.38 for PP3. SpliceAI max delta score is 0.03, well below the threshold. REVEL is not available for this synonymous variant. No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.03 (DS_AG=0.03
- DS_AL=0.0
- DS_DG=0.01
- DS_DL=0.0)
- REVEL: not applicable (synonymous variant)
- BayesDel: not applicable (synonymous variant)
Sources
BA1 The RUNX1 VCEP BA1 threshold requires MAF ≥ 0.0015 (0.15%) in any general continental population dataset with ≥2,000 alleles and ≥5 alleles. The highest observed subpopulation frequency is 8.48e-7 (0.000085%) in European (non-Finnish) with only 1 allele observed, far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 NFE AF = 8.48e-7 (1/1
- 179
- 858)
- Highest population AF far below VCEP BA1 threshold of 0.0015
- Only 1 allele observed (need ≥5 for BA1)
Sources
BS1 The RUNX1 VCEP BS1 threshold requires MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any population dataset with ≥2,000 alleles and ≥5 alleles. The gnomAD v4.1 total AF is 6.26e-7 (0.00006%) with 1 allele observed, below the BS1 lower bound. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF = 6.26e-7 (0.00006%)
- Below VCEP BS1 lower bound of 0.00015
- Only 1 allele observed (need ≥5 for BS1)
Sources
BS3 No functional study (transactivation assay demonstrating normal function, or secondary assay showing normal function) specifically evaluating c.30C>T has been identified. In silico predictions alone do not qualify for BS3. Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating normal function identified
Still missing
- No functional assay data available for this variant
Sources
2361927523652378256267072573023023169492
BS4 No verified observation of c.30C>T failing to segregate with disease in ≥2 informative meioses has been identified. Claims from the exploratory search attributing segregation data to specific publications could not be confirmed on full-text review; the cited PMIDs are about unrelated topics (newborn screening policy) and do not mention RUNX1 or this variant. Details ▾Hide ▴
Evidence considered
- No verified lack of segregation in informative meioses identified
Still missing
- No confirmed segregation data in families with RUNX1-associated disorders
Sources
230379332361927523652378256267072573023023169492
BP2 No observation of c.30C>T in trans with a known pathogenic RUNX1 variant has been identified. No homozygous state reported in individuals without FPD/AML phenotype. Details ▾Hide ▴
Evidence considered
- No in trans or homozygous observations identified
Still missing
- No compound heterozygous or homozygous genotype data available
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001001890.2:c.30C>T is a synonymous variant (p.Ser10=) in exon 1 and does not meet any null-variant criterion (nonsense, frameshift, canonical ±1,2 splice) under the RUNX1 MM-VCEP PVS1 decision tree or generic ClinGen SVI PVS1 recommendations. Details ▾Hide ▴
Evidence considered
- Synonymous variant producing no amino acid change
- not a null variant
Sources
PS1 N/ASynonymous variant (p.Ser10=) does not change the amino acid; PS1 requires the same amino acid change as a known pathogenic variant. Details ▾Hide ▴
PM3 VCEPSkipped per instruction. RUNX1-associated disorders are autosomal dominant; PM3 applies to recessive disorders. Details ▾Hide ▴
Evidence considered
- RUNX1 is an autosomal dominant disease gene
PM4 N/ASkipped per instruction. PM4 applies to in-frame deletions/insertions and stop-loss variants; c.30C>T is a synonymous substitution. Details ▾Hide ▴
Evidence considered
- Substitution variant
- PM4 applies to in-frame indels and stop-loss variants
PM5 N/APM5 requires a missense change at the same residue as a known pathogenic missense variant. c.30C>T is a synonymous variant (p.Ser10=) with no amino acid change; the variant class is not missense-like. The PM5 candidate assessment confirms no eligibility. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- no amino acid change at codon 10
- not eligible for same-residue missense PM5
Sources
pm5_candidatescspec ↗
PP2 VCEPPP2 is marked Not Applicable by the RUNX1 MM-VCEP v3.1.0. Details ▾Hide ▴
PP4 VCEPUnder the RUNX1 MM-VCEP v3.1.0, PP4 is marked Not Applicable because the FPD/AML phenotype is not sufficiently specific for a single genetic etiology. Details ▾Hide ▴
PP5 VCEPUnder the RUNX1 MM-VCEP v3.1.0, PP5 is explicitly marked Not Applicable for this VCEP per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
BS2 VCEPBS2 is marked Not Applicable by the RUNX1 MM-VCEP v3.1.0. Details ▾Hide ▴
BP1 VCEPBP1 is marked Not Applicable by the RUNX1 MM-VCEP v3.1.0. Details ▾Hide ▴
BP3 VCEPSkipped per instruction. In-frame indel criterion, not applicable to a substitution variant. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 applies to in-frame indels
BP5 VCEPBP5 is marked Not Applicable by the RUNX1 MM-VCEP v3.1.0. Details ▾Hide ▴
PS5 N/AUnder the RUNX1 MM-VCEP v3.1.0, the PP5/PS5 criterion is explicitly marked Not Applicable for this VCEP per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
Identifiers
- Gene
- RUNX1
- Transcript
- NM_001001890.2
- Coding (HGVS c.)
- NM_001001890.2:c.30C>T
- Protein (HGVS p.)
- NP_001001890.1:p.(Ser10=)
- GRCh38
- chr21:34887083 G>A
- GRCh37
- chr21:36259380 G>A
- ClinVar
- 532683
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
1 / 1,598,264 alleles
AF 6.26e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 6.3e-07 · 1 / 1,598,264 alleles · 0 hom
| European (non-Finnish)1 / 1,179,858 | 8.5e-07 |
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.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.25679e-07; MAF= 0.00006%, 1/1598264 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4756e-07; MAF= 0.00008%, 1/1179858 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingFor synonymous variants, the RUNX1 VCEP applies BP4 when SpliceAI ≤ 0.20. SpliceAI max delta score for c.30C>T is 0.03, well below the 0.20 threshold, predicting no impact on splicing. REVEL is not applicable for this synonymous variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.03 (well below BP4 threshold of 0.20)
- No predicted splice-altering effect
Sources
BP7 Supportingc.30C>T is a synonymous variant in exon 1 at CDS position 30, located 240 nucleotides upstream of the exon 1 donor splice site (c.270). It is not within the last 3 nucleotides preceding a canonical donor or the first nucleotide following a canonical acceptor. SpliceAI max delta is 0.03, well below the VCEP BP7 threshold of ≤0.20. The variant meets all BP7 criteria under the RUNX1 VCEP. Details ▾Hide ▴
Evidence considered
- Synonymous variant (p.Ser10=) not in exonic splice consensus region
- SpliceAI max delta = 0.03 (≤0.20 threshold)
- Located at c.30
- far from exon 1 donor site at c.270
Sources
PP3 For synonymous variants, the RUNX1 VCEP requires SpliceAI ≥ 0.38 for PP3. SpliceAI max delta score is 0.03, well below the threshold. REVEL is not available for this synonymous variant. No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.03 (DS_AG=0.03
- DS_AL=0.0
- DS_DG=0.01
- DS_DL=0.0)
- REVEL: not applicable (synonymous variant)
- BayesDel: not applicable (synonymous variant)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
13 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 23619275 ↗ACMG position statement on prenatal/preconception expanded carrier screening.No paper-specific finding is recorded.
-
PMID 23652378 ↗A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.Cornel MC et al. · 2014No paper-specific finding is recorded.
-
PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Howard HC et al. · 2015No paper-specific finding is recorded.
-
PMID 25730230 ↗Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.Edwards JG et al. · 2015No paper-specific finding is recorded.
-
PMID 23169492 ↗The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes.Fears R et al. · 2013No paper-specific finding is recorded.
-
PMID 24121147 ↗Appropriateness of newborn screening for α1-antitrypsin deficiency.Teckman J et al. · 2014No paper-specific finding is recorded.
-
PMID 33661592 ↗PMID:33661592No paper-specific finding is recorded.
-
PMID 22947299 ↗Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.Langer A et al. · 2012No paper-specific finding is recorded.
-
PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.Therrell BL et al. · 2013No paper-specific finding is recorded.
-
PMID 23881473 ↗Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.Blout C et al. · 2014No paper-specific finding is recorded.
-
PMID 24022298 ↗Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].Skirton H et al. · 2014No paper-specific finding is recorded.
-
PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.Botkin JR et al. · 2014No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,598,264 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
2 Likely benign
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/532683/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/21-36259380-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr21-34887083-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001001890.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/RUNX1/S10=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RUNX1+c.30C%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
This variant is present in gnomAD v4.1 (AF= 6.25679e-07; MAF= 0.00006%, 1/1598264 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4756e-07; MAF= 0.00008%, 1/1179858 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Likely Benign by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 532683)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
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.