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 v3.1.0.1 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 v2.1.2 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.3 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).4
RUNX1
Final classification
VUS
RUNX1 c.30C>T · p.Ser10=
RUNX1
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.
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.
Classification rationale
PM2
BP4BP6BP7
VUS
RUNX1 c.30C>T
PM2 + BP4 + BP6 + BP7
→
VUS
4
cspec ↗final_classification_framework
Gene diagram
· NM_001001890.2 · variants mapped to exon structure
RUNX1
NM_001001890.2
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 12 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v4.1: AF=6.26e-7 (1/1598264 alleles
✓
BP4
supporting
Benign
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.
SpliceAI max delta = 0.03 (well below BP4 threshold of 0.20)No predicted splice-altering effect
✓
✓
BP7
supporting
Benign
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.
Synonymous variant (p.Ser10=) not in exonic splice consensus regionSpliceAI max delta = 0.03 (≤0.20 threshold)Located at c.30
Assessed · not applied
Pathogenic
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.
PS3
No functional assay (transactivation, minigene splicing, or secondary assay) specifically assessing c.30C>T has been identified.
PS4
No probands meeting RUNX1-phenotypic criteria have been identified in any verified publication specifically reporting c.30C>T.
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).
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.
PP1
No co-segregation data (meioses observed within families with FPD/AML) has been identified for c.30C>T in any verified publication.
PP3
For synonymous variants, the RUNX1 VCEP requires SpliceAI ≥ 0.38 for PP3.
Benign
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.
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.
BS3
No functional study (transactivation assay demonstrating normal function, or secondary assay showing normal function) specifically evaluating c.30C>T has been identified.
BS4
No verified observation of c.30C>T failing to segregate with disease in ≥2 informative meioses has been identified.
BP2
No observation of c.30C>T in trans with a known pathogenic RUNX1 variant has been identified.
N/A · 12
PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS2 · BP1 · BP3 · BP5
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.3e-05%
· 1 / 1,598,264
0 hom
0 hom
European (non-Finnish) 1 / 1,179,858 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 13 PMIDs not cited in assessment
23652378 ↗
A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.
CLINVAR
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
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.
CLINVAR
23169492 ↗
The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes.
CLINVAR
22947299 ↗
Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.
CLINVAR
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.
CLINVAR
23881473 ↗
Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.
CLINVAR
24022298 ↗
Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].
CLINVAR
24394680 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR