Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001754.3 | Alternative | 6190 nt | 400–1842 |
| NM_001754.4 | RefSeq Select | 5967 nt | 191–1633 |
| NM_001754.5 | MANE Select | 5971 nt | 195–1637 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The RUNX1 G50Rfs*88 variant is a truncating mutation in the RUNX1 gene, a known tumor suppressor involved in hematopoietic differentiation. Functional evidence indicates that truncating mutations in RUNX1 disrupt its function, contributing to oncogenesis and predisposing individuals to hematologic malignancies such as leukemia, lymphomas, and myelodysplastic syndromes.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.1 | 50 bp |
| Donor Loss (DL) | 0.03 | 245 bp |
| Acceptor Gain (AG) | 0.0 | 105 bp |
| Donor Gain (DG) | 0.0 | -324 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Strength: Very Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.' The evidence for this variant shows: a truncating frameshift (c.147dupA; p.G50Rfs*88) in RUNX1, a gene where loss-of-function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because it is a null variant predicted to undergo nonsense‐mediated decay or result in LOF.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: it is a frameshift (G50Rfs*88), not a missense change matching a known pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Moderate Strength: Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity.” For each proven de novo case give 0.5 points; for each assumed de novo case give 0.25 points. Moderate = 1.0 points total.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'Not applicable if variant meets PVS1.' The evidence for this variant shows: PVS1 is met. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Supporting Strength: 1 proband meeting at least one of the RUNX1-phenotypic criteria; Moderate Strength: 2–3 probands; Strong Strength: ≥4 probands.' The evidence for this variant shows: no proband count data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Moderate Strength: Variant affecting one of the following amino acid residues within the RHD (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204); Supporting Strength: Variant affecting one of the other residues 89–204 within the RHD.' The evidence for this variant shows: p.G50Rfs*88 occurs at amino acid position 50, outside the RHD (89–204). Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Variant must be completely absent from all population databases.' The evidence for this variant shows: absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: no allelic phase (cis/trans) information available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Moderate Strength: In-frame deletion/insertion impacting specific RHD residues; Supporting Strength: In-frame deletion/insertion impacting other residues 89–204 within the RHD.' The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Supporting)
According to VCEP guidelines, the rule for PM5 is: 'Supporting Strength: PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4).' The evidence for this variant shows: frameshift at c.147dupA, which is downstream of c.98. Therefore, this criterion is applied at Supporting strength because it is a truncating variant downstream of the specified position.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: 'Moderate Strength: Phenotypic specificity category...Moderate = 1.0 points; Supporting = 0.5 points.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Supporting Strength: 3–4 meioses; Moderate Strength: 5–6 meioses; Strong Strength: ≥7 meioses.' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene that has a low rate of benign missense variants and where missense variants are a common mechanism of disease.' The evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Supporting Strength: For missense variants: REVEL ≥ 0.88; for missense, synonymous and intronic (intron 4–8): SpliceAI ≥ 0.38.' The evidence for this variant shows: it is a frameshift and does not meet missense or splice thresholds. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no clinical phenotype information available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic or likely pathogenic but evidence not available.' The evidence for this variant shows: not found in ClinVar. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: MAF ≥ 0.0015 in any general continental population dataset with ≥ 2,000 alleles tested.' The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong Strength: MAF between 0.00015 and 0.0015 in any general continental population dataset with ≥ 2,000 alleles tested.' The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a fully penetrant dominant gene/disorder.' The evidence for this variant shows: no data in healthy individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong Strength: Transactivation assays demonstrating normal transactivation (80–115% of wt) AND a secondary assay demonstrating normal function; Supporting Strength: Transactivation assays demonstrating normal transactivation (80–115% of wt).' The evidence for this variant shows: no functional assays demonstrating normal function. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members of a family.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which loss-of-function is a known mechanism of disease and missense variants are not a common mechanism.' The evidence for this variant shows: it is a frameshift LOF variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder.' The evidence for this variant shows: no data on cis/trans. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame insertions/deletions in a repetitive region without a known function.' The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: For missense variants: REVEL < 0.50 AND SpliceAI ≤ 0.20; for synonymous and intronic variants: SpliceAI ≤ 0.20.' The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign but evidence not available.' The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting Strength: Synonymous and intronic variants with SpliceAI ≤ 0.20 AND phyloP100way ≤ 2.0.' The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.