RUNX1 c.501_508dup, p.Gly170ValfsTer9
NM_001754.4:c.501_508dup
Pathogenic
This RUNX1 frameshift variant (G170Vfs*9) introduces a premature stop codon, is absent from population databases, meets VCEP PVS1 Very Strong, and has supporting PM2, PM5, and PP3 evidence. Collectively, this fulfills criteria for Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PM2
PM5
PP3
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.501_508dup
Protein Change
G170Vfs*9
Location
Exon 5
(Exon 5 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 170 in gene RUNX1
Variant interpretation based on transcript NM_001754.5
Genome Browser
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HGVS InputNM_001754:c.501_508dup
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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 170 in gene RUNX1
Functional Summary
The RUNX1 G170Vfs*9 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 typically inhibit 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. Modification Type: Gene-specific". The evidence for this variant shows a frameshift resulting in a premature termination codon (G170Vfs*9) in RUNX1, a gene where loss of function is a known mechanism and not located in the last exon. Therefore, this criterion is applied at Very Strong strength because this is a null variant in a gene with established LOF disease mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. The evidence for this variant shows a unique frameshift (G170Vfs*9) with no prior identical amino acid change reported as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 requires proven or assumed de novo occurrence scoring against phenotypic specificity. There is no data on de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 is not applicable if a variant meets PVS1. The evidence for this variant meets PVS1. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires multiple probands meeting RUNX1-associated phenotypic criteria. There are no reported proband counts for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants affecting specific RHD residues. This variant is a frameshift, not a missense change. 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. Modification Type: Strength". The evidence for this variant shows it is absent from gnomAD and other population databases. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to variants detected in trans with a pathogenic variant in a recessive disorder. RUNX1-related disease is autosomal dominant and there is no evidence of compound heterozygosity. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, PM4 applies to in-frame insertions or deletions in the RHD. This variant is a frameshift duplication, not an in-frame event. 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). Modification Type: Strength". The evidence for this variant shows a frameshift at c.501_508dup (downstream of c.98). Therefore, PM5 is applied at Supporting strength.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 requires assumed or proven de novo cases. There is no de novo data for this variant. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation with disease in multiple affected family members. No segregation data are available for this variant. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in a gene with low benign variation rate. This variant is a frameshift event. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: For missense, synonymous and intronic (intron 4-8) variants: SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites. Modification Type: Gene-specific,Disease-specific". The evidence for this variant shows a SpliceAI maximum score of 1.0 predicting high impact on splicing. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires patient phenotype specificity consistent with RUNX1-related disease. No clinical phenotype information is provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 (reputable source) is not recommended for use. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires a minor allele frequency ≥ 0.15% in general populations. The variant is absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 requires MAF between 0.015% and 0.15%. The variant is absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 requires observation in healthy adult individuals with full penetrance. No such data exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires functional assays demonstrating normal function. No such data exist for this variant. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires segregation data inconsistent with pathogenicity. No segregation data exist. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in a gene where only truncating variants are pathogenic. This is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 requires observation in trans with a pathogenic variant in a fully penetrant dominant gene or in cis, which is not documented. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This variant is a frameshift outside of a known repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires benign computational evidence (SpliceAI ≤ 0.20 and REVEL < 0.50). SpliceAI is 1.0. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such context is provided. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 (reputable source) is not recommended for use. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with SpliceAI ≤ 0.20. This is a coding frameshift. Therefore, this criterion is not applied.