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 Y355* variant is a truncating mutation in a tumor suppressor gene, likely resulting in loss of function. Functional evidence indicates that such truncating mutations in RUNX1 inhibit its role in hematopoietic differentiation, predisposing to hematologic malignancies.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 97 bp |
| Donor Loss (DL) | 0.0 | 297 bp |
| Acceptor Gain (AG) | 0.0 | -181 bp |
| Donor Gain (DG) | 0.0 | -189 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 frameshift/nonsense truncating mutation (Y355*) in RUNX1, a gene where loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is predicted to result in loss of function in a gene with LOF pathogenicity.
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 no previously established pathogenic variant causing Y355*. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Moderate/Supporting de novo evidence based on points for proven or assumed cases." The evidence for this variant provides no parental testing or de novo confirmation. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, "PS3 is not applicable if variant meets PVS1." The evidence shows the variant meets PVS1. Therefore, PS3 is not applied despite functional data because PVS1 supersedes PS3 in VCEP RUNX1 rules.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 Strong is: "≥4 probands meeting at least one of the RUNX1-phenotypic criteria." The evidence presents no case counts or phenotypic cohort data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 Moderate is: "Variant affecting one of the specified RHD residues (R107, K110, …, R204)." The evidence shows Y355* lies outside the RHD region (residues 89–204). Therefore, PM1 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 shows the variant is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." There is no evidence of a second allele or recessive inheritance for this variant. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 applies to in-frame insertions/deletions. This variant is a frameshift duplication. Therefore, PM4 is not applied.
PM5 (Supporting)
According to VCEP guidelines, the rule for PM5 Supporting is: "PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 in transcript NM_001754.4." The evidence shows this Y355* truncating variant is at c.1064 (downstream of c.98). Therefore, PM5 is applied at Supporting strength.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo cases scored similar to PS2." No de novo or assumed de novo data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 Supporting is: "3–4 meioses observed with co-segregation." No family segregation data are provided. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a truncating duplication. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 Supporting is: "REVEL ≥0.88 for missense or SpliceAI ≥0.38 for splicing." The variant is truncating and SpliceAI score is 0, not applicable. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 applies when phenotype is highly specific and consistent. No detailed clinical phenotype data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies based on reputable source assertions without available evidence. No such assertions exist. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies to variants with MAF ≥0.15%. The variant is absent from population databases. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies to variants with MAF between 0.015%–0.15%. The variant is absent. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 applies when variant is observed in healthy adult individuals. No such data exist. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 applies when functional studies demonstrate normal function. Available studies show loss of function. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 applies when variant does not segregate with disease in multiple meioses. No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. This variant is truncating. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies to variants observed in trans with a pathogenic variant in dominant genes. No such data exist. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a frameshift duplication. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 Supporting is: "REVEL <0.50 and/or SpliceAI ≤0.20 for missense/synonymous/intronic." The variant is truncating and SpliceAI is 0 but BP4 does not apply to truncating variants. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when variant is found in trans with a pathogenic variant for a fully penetrant dominant gene. No such data exist. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies based on other source assertions of benign. No such assertions exist. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 applies to synonymous/intronic variants with SpliceAI ≤0.20 and low conservation. This variant is truncating. Therefore, BP7 is not applied.