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 S322Ffs*278 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 can inhibit its function, contributing to oncogenesis and predisposing 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) | 0.0 | None bp |
| Donor Loss (DL) | 0.0 | None bp |
| Acceptor Gain (AG) | 0.0 | None bp |
| Donor Gain (DG) | 0.0 | None 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." The evidence for this variant shows: c.964dupT causes a frameshift leading to a premature stop codon (S322Ffs*278), a null variant in RUNX1 not in the last exon, where loss‐of‐function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because it is a truncating variant meeting the VCEP PVS1 decision tree.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies when the same amino acid change as a previously established pathogenic variant occurs. The evidence for this variant shows: S322Ffs*278 is a novel frameshift, not a recurrence of a known pathogenic amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, PS2 (de novo) requires proven or assumed de novo occurrence. The evidence for this variant shows: parental origin data are unavailable. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 is not applicable if a variant meets PVS1. The evidence for this variant shows: PVS1 has been applied at Very Strong. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 requires ≥4 probands (Strong), 2–3 probands (Moderate), or 1 proband (Supporting) meeting RUNX1-phenotypic criteria. The evidence for this variant shows: no proband data reported. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies to variants affecting specific residues within the RHD. The evidence for this variant shows: S322Ffs*278 lies outside the RHD (residues 50–182). 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 for this variant shows: c.964dupT is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is completely absent.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies when a variant occurs in trans with a pathogenic variant for a recessive disorder. The evidence for this variant shows: no data on trans observations or recessive context. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, PM4 applies to in-frame indels in the RHD. The evidence for this variant shows: c.964dupT 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: "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: c.964dupT is downstream of c.98 and causes a frameshift. Therefore, this criterion is applied at Supporting strength because it meets the VCEP PM5_supporting rule.
PM6 (Not Applied)
According to VCEP guidelines, PM6 (assumed de novo) requires de novo occurrence data. The evidence for this variant shows: no parental data available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 requires co-segregation with disease in families. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation. The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 applies to computational evidence for missense or splice-impact. The evidence for this variant shows: it is a truncating frameshift, not applicable for computational missense/splice prediction. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 requires a highly specific phenotype. The evidence for this variant shows: detailed clinical phenotype data are not provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic. The evidence for this variant shows: no ClinVar or similar submission. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, BA1 requires MAF ≥0.15% in any population. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, BS1 requires MAF between 0.015% and 0.15%. The evidence for this variant shows: absent from databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 applies when variant observed in healthy adults. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires normal functional assay results. The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 requires lack of segregation in affected members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense in genes where only LOF is disease mechanism. The evidence for this variant shows: it is LOF. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when observed in trans with a pathogenic variant. The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows: frameshift, not in repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 requires computational evidence of benign impact. The evidence for this variant shows: frameshift causing LOF. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when variant found in a case with an alternate molecular cause. The evidence for this variant shows: no alternate cause reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies when a reputable source reports variant as benign. The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. The evidence for this variant shows: it is a frameshift, not synonymous. Therefore, this criterion is not applied.