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
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 243 bp |
| Donor Loss (DL) | 0.0 | -173 bp |
| Acceptor Gain (AG) | 0.04 | 201 bp |
| Donor Gain (DG) | 0.02 | 396 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the PVS1 rule is: "Very Strong Strength: Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects." The evidence for this variant shows an in-frame deletion of a single codon (C99del), which is not a null variant (nonsense, frameshift, canonical ±1/2 splice site, start codon loss, or exon deletion). Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the PS1 rule is: "Strong Strength: 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 with the same cysteine 99 deletion. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the PS2 rule is: "Moderate Strength: For each proven de novo case give 0.5 points; for each assumed de novo case give 0.25 points; total 1.0 needed for Moderate." The evidence for this variant shows no confirmed de novo occurrences. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the PS3 rules are: "Strong Strength: Transactivation assays demonstrating altered function with secondary assay; Moderate Strength: transactivation OR ≥2 secondary assays; Supporting Strength: enhanced transactivation." The evidence for this variant shows no functional studies. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the PS4 rules are: "Strong Strength: ≥4 probands; Moderate Strength: 2–3 probands; Supporting Strength: 1 proband." The evidence for this variant shows no reported probands meeting RUNX1-phenotypic criteria. Therefore, this criterion is not applied.
PM1 (Supporting)
According to VCEP guidelines, the PM1 rule is: "Supporting Strength: Variant affecting one of the other amino acid residues 89–204 within the RHD." The evidence for this variant shows an in-frame deletion at codon 99, which lies within residues 89–204 of the RHD. Therefore, this criterion is applied at Supporting strength.
PM2 (Supporting)
According to VCEP guidelines, the PM2 rule is: "Supporting Strength: Variant must be completely absent from all population databases." The evidence for this variant shows it is not present in gnomAD or other control databases. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the PM3 rule applies to recessive disorders when in trans with a pathogenic variant. The evidence for this variant shows no trans observations with a pathogenic RUNX1 variant. Therefore, this criterion is not applied.
PM4 (Supporting)
According to VCEP guidelines, the PM4 rule is: "Supporting Strength: In-frame deletion/insertion impacting at least one of the other amino acid residues 89–204 within the RHD." The evidence for this variant shows an in-frame deletion at codon 99 within the RHD. Therefore, this criterion is applied at Supporting strength.
PM5 (Not Applied)
According to VCEP guidelines, the PM5 rules apply to missense changes at residues with established pathogenic missense variants or to downstream nonsense/frameshift. This variant is an in-frame deletion, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the PM6 rule is: "Moderate Strength: de novo cases scoring to 1.0 points total for assumed/proven de novo." The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the PP1 rules are: "Supporting Strength: 3–4 informative meioses; Moderate Strength: 5–6 meioses; Strong Strength: ≥7 meioses." The evidence for this variant shows no family segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies when a missense variant is in a gene with low rate of benign missense variation. This variant is an in-frame deletion, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the PP3 rule is: "Supporting Strength: For missense variants, REVEL ≥0.88 or SpliceAI ≥0.38." The evidence for this variant shows a SpliceAI score of 0.04 and no REVEL score, and PP3 is for missense/intronic variants only. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 applies when phenotype is highly specific to a gene. No phenotype data are provided for this variant. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies when multiple reputable sources report the variant as pathogenic. This variant is not present in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the BA1 rule is: "Stand Alone Strength: allele frequency ≥0.15% in general population datasets." The evidence for this variant shows MAF = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the BS1 rule is: "Strong Strength: allele frequency between 0.015% and 0.15%." The evidence for this variant shows MAF = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 applies when observed in a healthy adult for a dominant disorder. No such observations exist for this variant. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the BS3 rules require functional assays demonstrating normal function. No functional studies exist for this variant. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the BS4 rule is: "Strong Strength: applied when seen in ≥2 informative meioses inconsistent with pathogenic segregation." No segregation data exist. Therefore, this criterion 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 is an in-frame deletion. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when observed in trans with a pathogenic variant in a dominant disorder. No such observations exist. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame deletions in repetitive regions without known function. This variant is within the RHD domain, not a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the BP4 rule is: "Supporting Strength: For missense variants REVEL <0.50 and SpliceAI ≤0.20; for synonymous/intronic SpliceAI ≤0.20." This variant is an in-frame deletion. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular basis. No such cases exist. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies when multiple reputable sources report the variant as benign. This variant is not reported in ClinVar. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the BP7 rule is: "Supporting Strength: for synonymous/intronic variants with SpliceAI ≤0.20 and phyloP ≤2.0." This variant is an in-frame deletion. Therefore, this criterion is not applied.