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 W106Vfs*17 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.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 218 bp |
| Donor Loss (DL) | 0.0 | -156 bp |
| Acceptor Gain (AG) | 0.01 | 353 bp |
| Donor Gain (DG) | 0.0 | 413 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 at Very Strong strength is: "Very Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects." The evidence for this variant shows: NM_001754.4:c.315_316insGT introduces a frameshift resulting in a premature termination codon in RUNX1, 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 consistent with the VCEP PVS1 rule.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 Strong strength is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: the c.315_316insGT frameshift does not result in the same amino acid change as any known pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point." The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 Strong strength is: "Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets PVS1. If variant meets PVS1_strong, either apply PS3_moderate or upgrade to PVS1." The evidence for this variant shows: it meets PVS1 and no specific transactivation assays were provided. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 Strong strength is: "≥ 4 probands meeting at least one of the RUNX1-phenotypic criteria." The evidence for this variant shows: no proband numbers or case series are reported. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 Supporting strength is: "Variant affecting one of the other amino acid residues 89-204 within the RHD." The evidence for this variant shows: NM_001754.4:c.315_316insGT is a frameshift, not a missense affecting a specific residue. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 at Supporting strength is: "Variant must be completely absent from all population databases." The evidence for this variant shows: it is absent from gnomAD and other large population datasets. Therefore, this criterion is applied at Supporting strength because the variant is completely absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for autosomal recessive disorders." The evidence for this variant shows: RUNX1‐related 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 Moderate strength is: "In-frame deletion/insertion impacting at least one of the following amino acid residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204." The evidence for this variant shows: NM_001754.4:c.315_316insGT is a frameshift insertion, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Supporting)
According to VCEP guidelines, the rule for PM5 Supporting strength 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: the frameshift occurs at codon 106, downstream of c.98. Therefore, this criterion is applied at Supporting strength because it meets the specific VCEP PM5 rule.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 Supporting strength is: "3–4 meioses observed within one or across multiple families." The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." 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, the rule for PP3 Supporting strength is: "For missense variants: REVEL score ≥ 0.88; For missense, synonymous and intronic (intron 4-8) variants: SpliceAI ≥ 0.38." The evidence for this variant shows: it is a frameshift, not a missense or splicing prediction issue. 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." The evidence for this variant shows: no phenotype information is provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic or likely pathogenic without available evidence." The evidence for this variant shows: it is not found in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 Stand Alone strength is: "Minor allele frequency between 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles." The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 Strong strength is: "Minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles." The evidence for this variant shows: it 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 adult individual for a fully penetrant dominant disorder." The evidence for this variant shows: no such observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 Strong strength is: "Transactivation assays demonstrating normal transactivation (80–115% of wt) AND data from a secondary assay demonstrating normal function." The evidence for this variant shows: no normal functional assay results are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 Strong strength is: "Applied when seen in ≥ 2 informative meioses." The evidence for this variant shows: 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 gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: it is itself a truncating variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 Supporting strength is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern." The evidence for this variant shows: no evidence of cis/trans observations with another pathogenic variant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertions/deletions in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift insertion, not an in-frame event. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 Supporting strength is: "For missense variants: REVEL score < 0.50 AND SpliceAI ≤ 0.20; For synonymous and intronic variants: SpliceAI ≤ 0.20." The evidence for this variant shows: it is a frameshift, not amenable to these in silico metrics. 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 for disease." The evidence for this variant shows: no alternate molecular basis 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 or likely benign without evidence." The evidence for this variant shows: no such reports are available. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 Supporting strength is: "Applicable for synonymous and intronic variants with SpliceAI ≤ 0.20 AND phyloP ≤ 2.0." The evidence for this variant shows: it is a frameshift, not synonymous or intronic. Therefore, this criterion is not applied.