Starting
Initialising…
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RUNX1
Final classification
VUS
RUNX1 c.624C>T · p.Ala208=
RUNX1

NM_001001890.2:c.624C>T (p.Ala208=) is a synonymous variant in exon 4 of RUNX1 that does not alter the amino acid sequence.

Gene
RUNX1
Transcript
NM_001001890.2
HGVS · transcript:coding
NM_001001890.2:c.624C>T
Consequence
N/A
GRCh38
chr21:34834510 G>A
GRCh37
chr21:36206807 G>A
Basis 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.
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.624C>T

NM_001001890.2:c.624C>T (p.Ala208=) is a synonymous variant in exon 4 of RUNX1 that does not alter the amino acid sequence. This variant is present at extremely low frequency in gnomAD (v4.1 grpmax FAF = 3.259e-05, 53/1,613,324 alleles), meeting PM2_Supporting under the MM-VCEP specification (MAF ≤0.00005).1 SpliceAI predicts no splice impact (max delta = 0.02), meeting BP4 (SpliceAI ≤0.20 for synonymous variants) under the MM-VCEP specification.2 The variant meets BP7 as a synonymous change not located in the critical splice region (not in the last 3 nucleotides of exon 4 nor the first nucleotide after the acceptor site), with SpliceAI ≤0.20.3 The ClinGen Myeloid Malignancy VCEP classified this variant as Likely Benign (ClinVar ID 532686, SCV001366061, reviewed by expert panel), consistent with the computed Tavtigian score of -1 (PM2_Supporting +1, BP4 -1, BP7 -1).4 No pathogenic evidence was identified: no de novo occurrences (PS2/PM6), no probands with FPD/AML phenotype (PS4), no functional data demonstrating damaging effect (PS3), no cosegregation data (PP1), the variant lies outside the RHD (PM1 not met), and in silico predictions do not support pathogenicity (PP3 not met).5 Population frequencies are too low to meet BA1 (>0.15%) or BS1 (0.015%-0.15%), but the variant is not absent from population databases.6 BS3 could not be independently assessed as the primary functional assay data reviewed by the expert panel is not publicly accessible through ClinVar; however, the expert panel's Likely Benign classification implies functional evidence was not supportive of pathogenicity.7

PM2 + BP4 + BP6 + BP7 VUS
Gene diagram · NM_001001890.2 · variants mapped to exon structure
RUNX1 NM_001001890.2
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 3.28514e-05; MAF= 0.00329%, 53/1613324 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23733e-05; MAF= 0.00424%, 50/1179988 alleles, homozygotes = 0); grpmax FAF= 3.259e-05.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 7.08275e-06; MAF= 0.00071%, 2/282376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.55072e-05; MAF= 0.00155%, 2/128972 alleles, homozygotes = 0).
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.0033% · 53 / 1,613,324
      0 hom · FAF 0.0033%
      European (non-Finnish)
      50 / 1,179,988
      0.0042%
      Remaining individuals
      2 / 62,456
      0.0032%
      South Asian
      1 / 91,060
      0.0011%
      + 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      0.00071% · 2 / 282,376
      0 hom
      European (non-Finnish)
      2 / 128,972
      0.0016%
      + 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      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 = 532686)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      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
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 14 PMIDs not cited in assessment
      23619275 ↗ ACMG position statement on prenatal/preconception expanded carrier screening. CLINVAR
      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
      24121147 ↗ Appropriateness of newborn screening for α1-antitrypsin deficiency. CLINVAR
      25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
      33661592 ↗ PMID:33661592 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