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 H206Qfs*7 variant is a truncating mutation in the RUNX1 gene, a tumor suppressor involved in hematopoietic differentiation. Functional evidence indicates that truncating mutations in RUNX1 inhibit its function, predisposing to hematologic malignancies such as leukemia, lymphomas, and myelodysplastic syndromes. This suggests a damaging effect of the variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.02 | -304 bp |
| Donor Loss (DL) | 0.02 | -454 bp |
| Acceptor Gain (AG) | 0.0 | -306 bp |
| Donor Gain (DG) | 0.0 | 290 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. Modification Type: Gene-specific". The evidence shows a c.617dupA frameshift in RUNX1 predicted to cause early truncation and loss of function in a gene where loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it is a null variant in RUNX1 consistent with VCEP PVS1 guidance.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence shows no previously established pathogenic variant causes the same amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Moderate Phenotypic specificity category: 'Phenotype consistent with gene but not highly specific and high genetic heterogeneity'...". There is no reported de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong Transactivation assays demonstrating altered transactivation... Not applicable if variant meets PVS1. If variant meets PVS1_strong, either apply PS3_moderate or upgrade to PVS1." The evidence shows the variant meets PVS1 at Very Strong strength. Therefore, PS3 is not applied due to the PVS1 precedence.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong ≥ 4 probands meeting at least one of the RUNX1-phenotypic criteria." No proband data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Moderate Variant affecting one of the following amino acid residues within the RHD: R107,...,R204." The variant affects H206, which is outside the specified RHD residues. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Variant must be completely absent from all population databases." The evidence shows c.617dupA is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 pertains to recessive inheritance: "Variant observed in trans with a pathogenic variant...". RUNX1 disorders are dominant and no trans observations are reported. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Moderate In-frame deletion/insertion impacting...". The variant is a frameshift duplication, not an in-frame change. Therefore, this criterion is not applied.
PM5 (Supporting)
According to VCEP guidelines, the rule for PM5 is: "Supporting: PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 in transcript NM_001754.4." The variant c.617dupA creates a frameshift downstream of c.98. Therefore, this criterion is applied at Supporting strength.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Moderate Phenotypic specificity category... For each proven de novo case...". There is no de novo evidence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting 3 or 4 meioses observed...". No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: missense variant in a gene with low rate of benign missense variation...". The variant is a frameshift, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting For missense variants: REVEL ≥ 0.88; For splice impact: SpliceAI ≥ 0.38." The variant is a frameshift and computational splice predictions are minimal. 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." No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: reputable source recently reports variant as pathogenic." There is no such report. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Minor allele frequency between 0.0015...". The variant is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Minor allele frequency between 0.00015 and 0.0015...". The variant is absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy individual...". No such observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong Transactivation assays demonstrating normal transactivation...". Functional data indicate damaging effect, not 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...". No segregation data are available. 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 primarily truncating variants cause disease." The variant is truncating. 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...". No such data are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions...". The variant is a frameshift. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "In silico evidence suggests no impact...". The variant is frameshift and predicted damaging. 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...". No such alternate cause is 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." No such report exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting BP7 is applicable for synonymous and intronic variants with SpliceAI ≤ 0.20...". The variant is a frameshift. Therefore, this criterion is not applied.