RUNX1 c.147dup, p.Gly50ArgfsTer88
NM_001754.4:c.147dup
Pathogenic
This variant is classified as Likely Pathogenic based on VCEP criteria: PVS1 at Very Strong strength plus two Supporting criteria (PM2 and PM5).
ACMG/AMP Criteria Applied
PVS1
PM2
PM5
Genetic Information
Gene & Transcript Details
Gene
RUNX1
Transcript
NM_001754.5
MANE Select
Total Exons
9
Strand
Reverse (−)
Reference Sequence
NC_000021.8
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001754.3 | Alternative | 8 exons | Reverse |
| NM_001754.4 | RefSeq Select | 9 exons | Reverse |
Variant Details
HGVS Notation
NM_001754.4:c.147dup
Protein Change
G50Rfs*88
Location
Exon 4
(Exon 4 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 50 in gene RUNX1
Variant interpretation based on transcript NM_001754.5
Genome Browser
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HGVS InputNM_001754:c.147dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 50 in gene RUNX1
Functional Summary
The RUNX1 G50Rfs*88 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 disrupt its function, contributing to oncogenesis and predisposing individuals to hematologic malignancies such as leukemia, lymphomas, and myelodysplastic syndromes.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
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 truncating frameshift (c.147dupA; p.G50Rfs*88) in RUNX1, a gene where loss-of-function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because it is a null variant predicted to undergo nonsense‐mediated decay or result in LOF.
PS1
PS1 (Not Applied) Strength Modified
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: it is a frameshift (G50Rfs*88), not a missense change matching a known pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Moderate Strength: 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 points. Moderate = 1.0 points total.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Not applicable if variant meets PVS1.' The evidence for this variant shows: PVS1 is met. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Supporting Strength: 1 proband meeting at least one of the RUNX1-phenotypic criteria; Moderate Strength: 2–3 probands; Strong Strength: ≥4 probands.' The evidence for this variant shows: no proband count data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate Strength: Variant affecting one of the following amino acid residues within the RHD (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204); Supporting Strength: Variant affecting one of the other residues 89–204 within the RHD.' The evidence for this variant shows: p.G50Rfs*88 occurs at amino acid position 50, outside the RHD (89–204). Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Variant must be completely absent from all population databases.' The evidence for this variant shows: absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: no allelic phase (cis/trans) information available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Moderate Strength: In-frame deletion/insertion impacting specific RHD residues; Supporting Strength: In-frame deletion/insertion impacting other residues 89–204 within the RHD.' The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Supporting Strength: 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: frameshift at c.147dupA, which is downstream of c.98. Therefore, this criterion is applied at Supporting strength because it is a truncating variant downstream of the specified position.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'Moderate Strength: Phenotypic specificity category...Moderate = 1.0 points; Supporting = 0.5 points.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting Strength: 3–4 meioses; Moderate Strength: 5–6 meioses; Strong Strength: ≥7 meioses.' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene that has a low rate of benign missense variants and where missense variants are a common mechanism of disease.' The evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting Strength: For missense variants: REVEL ≥ 0.88; for missense, synonymous and intronic (intron 4–8): SpliceAI ≥ 0.38.' The evidence for this variant shows: it is a frameshift and does not meet missense or splice thresholds. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
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 clinical phenotype information available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic or likely pathogenic but evidence not available.' The evidence for this variant shows: not found in ClinVar. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: MAF ≥ 0.0015 in any general continental population dataset with ≥ 2,000 alleles tested.' The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong Strength: MAF between 0.00015 and 0.0015 in any general continental population dataset with ≥ 2,000 alleles tested.' The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a fully penetrant dominant gene/disorder.' The evidence for this variant shows: no data in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong Strength: Transactivation assays demonstrating normal transactivation (80–115% of wt) AND a secondary assay demonstrating normal function; Supporting Strength: Transactivation assays demonstrating normal transactivation (80–115% of wt).' The evidence for this variant shows: no functional assays demonstrating normal function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 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
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which loss-of-function is a known mechanism of disease and missense variants are not a common mechanism.' The evidence for this variant shows: it is a frameshift LOF variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder.' The evidence for this variant shows: no data on cis/trans. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
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. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: For missense variants: REVEL < 0.50 AND SpliceAI ≤ 0.20; for synonymous and intronic variants: SpliceAI ≤ 0.20.' The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
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 reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign but evidence not available.' The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting Strength: Synonymous and intronic variants with SpliceAI ≤ 0.20 AND phyloP100way ≤ 2.0.' The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.