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 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 it is an in-frame single amino acid deletion (C99del), not a null frameshift or canonical ±1/2 splice site. Therefore, this criterion is not applied because the variant does not meet the definition of a loss-of-function null variant.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 Strong is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no prior pathogenic variant resulting in C99del reported. Therefore, this criterion is not applied because there is no known pathogenic variant with the identical amino acid change.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 Moderate is: "Phenotype consistent with gene but not highly specific and high genetic heterogeneity. For each proven de novo case give 0.5 points…Moderate = 1.0 points total." The evidence for this variant shows no de novo status has been established. Therefore, this criterion is not applied due to absence of de novo data.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 Strong is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows no functional studies have been performed. Therefore, this criterion is not applied because required functional data are missing.
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 for this variant shows no proband data. Therefore, this criterion is not applied due to lack of case data.
PM1 (Supporting)
According to VCEP guidelines, the rule for PM1 Supporting is: "Variant affecting one of the other amino acid residues 89-204 within the RHD." The evidence for this variant shows deletion of C99, which lies between residues 89 and 204 in the Runt Homology Domain. Therefore, this criterion is applied at Supporting strength because the variant affects a non-hotspot residue within the critical domain.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 Supporting is: "Variant must be completely absent from all population databases." The evidence for this variant shows it is not present in gnomAD or other control datasets. Therefore, this criterion is applied at Supporting strength due to absence from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 Moderate is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows no information on trans phase with another variant. Therefore, this criterion is not applied.
PM4 (Supporting)
According to VCEP guidelines, the rule for PM4 Supporting is: "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 of codon 99, which is within residues 89-204. Therefore, this criterion is applied at Supporting strength because it is an in-frame deletion in the domain outside the specific hotspot residues.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 Moderate is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows it is an in-frame deletion, not a missense change at a residue with known pathogenic missense variants. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 Moderate is: "Phenotype consistent with gene…for each assumed de novo case give 0.25 points…Moderate = 1.0 points total." The evidence for this variant shows no de novo information. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 Supporting is: "3 or 4 meioses observed within one or across multiple families." The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 Supporting is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows it is an in-frame deletion, not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 Supporting is: "For missense variants: REVEL ≥ 0.88 or SpliceAI ≥ 0.38…" The evidence for this variant shows it is an in-frame deletion and SpliceAI score is 0.04. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 Supporting 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 phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 Supporting is: "Reputable source recently reports variant as pathogenic." The evidence for this variant shows no ClinVar or other report. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 Stand Alone is: "Minor allele frequency ≥ 0.15% in any general population dataset." The evidence for this variant shows it is absent from all population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 Strong is: "Minor allele frequency between 0.015% and 0.15% in any general population dataset." 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 Strong is: "Observed in a healthy adult individual for a dominant disorder with full penetrance." The evidence for this variant shows no healthy adult observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 Strong is: "Transactivation assays demonstrating normal function AND secondary assay normal." The evidence for this variant shows no functional assays. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 Strong 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 Supporting is: "Missense variant in a gene where only loss-of-function causes disease." The evidence for this variant shows an in-frame deletion. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 Supporting is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene." The evidence for this variant shows no such observation. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 Supporting is: "In-frame deletion in a repetitive region without known function." The evidence for this variant shows no repetitive region context. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 Supporting is: "For missense variants REVEL < 0.50 and SpliceAI ≤ 0.20." The evidence for this variant shows an in-frame deletion. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 Supporting is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows no alternate diagnosis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 Supporting is: "Reputable source reports variant as benign." The evidence for this variant shows no such report. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 Supporting is: "Synonymous or intronic variant with SpliceAI ≤ 0.20 and phyloP100way ≤ 2.0." The evidence for this variant shows it is an in-frame coding deletion. Therefore, this criterion is not applied.