RUNX1 c.489dup, p.Val164CysfsTer49
NM_001754.4:c.489dup
COSMIC ID: COSM10548754
Pathogenic
This RUNX1 c.489dup (p.Val164Cysfs*49) frameshift variant leads to loss-of-function in a gene with LOF disease mechanism, is absent from population databases, meets gene-specific VCEP PVS1 (Very Strong), PM2 (Supporting), PM5 (Supporting), and PP5 (Supporting) criteria, resulting in a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PM2
PM5
PP5
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.489dup
Protein Change
V164Cfs*49
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 164 in gene RUNX1
Alternate Identifiers
COSM10548754
Variant interpretation based on transcript NM_001754.5
Genome Browser
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HGVS InputNM_001754:c.489dup
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
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories) and as Pathogenic by ClinGen Myeloid Malignancy Variant Curation Expert Panel expert panel.
Expert Panel Reviews
Pathogenic
ClinGen Myeloid Malignancy Variant Curation Expert Panel
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 164 in gene RUNX1
Functional Summary
The RUNX1 V164Cfs*49 variant is a truncating mutation in a tumor suppressor gene, likely resulting in loss of function. Functional evidence indicates that truncating mutations in RUNX1 inhibit its function, predisposing 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 for RUNX1, 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: a frameshift (c.489dup) resulting in premature truncation (p.Val164Cysfs*49) not located in the last exon. Therefore, this criterion is applied at Very Strong strength because a null variant in RUNX1 is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, PS1 applies when the same amino acid change as a previously established pathogenic variant exists. The evidence for this variant shows: a unique frameshift, not matching any established amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence with parental testing. 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 for RUNX1, PS3 is not applicable if the variant meets PVS1. Although functional studies demonstrate loss of function, VCEP specifies PS3 should not be applied when PVS1 is met. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, PS4 requires case counts (≥4 probands for Strong, 2–3 for Moderate, 1 for Supporting). The evidence for this variant shows: no published proband aggregation data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, PM1 applies to missense or in‐frame changes in the RHD domain. The evidence for this variant shows: a frameshift outside of domain‐specific missense context. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for RUNX1, PM2 at Supporting strength is: "Variant must be completely absent from all population databases." The evidence for this variant shows: absent from gnomAD and other population datasets (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to variants observed in trans with a pathogenic variant in a recessive disorder. The evidence for this variant shows: no evidence of recessive inheritance or trans observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, PM4 applies to in‐frame insertions/deletions in the RHD. The evidence for this variant shows: a frameshift leading to truncation, not an in‐frame event. Therefore, this criterion is not applied.
PM5
PM5 (Supporting) Strength Modified
According to VCEP guidelines for RUNX1, PM5_supporting is applied to nonsense/frameshift variants downstream of c.98 in transcript NM_001754.4. The evidence for this variant shows: c.489dup causing frameshift at p.Val164Cysfs*49, downstream of c.98. Therefore, this criterion is applied at Supporting strength.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, PM6 requires assumed de novo cases with scoring. 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 for RUNX1, PP1 assesses segregation in multiple affected family members. 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, PP2 applies to missense variants in genes with low benign missense rate. The evidence for this variant shows: a truncating frameshift. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, PP3 applies to in silico predictions for missense or splice impact (SpliceAI ≥0.38). The evidence for this variant shows: frameshift variant not assessed by PP3. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires highly specific phenotype consistent with a single gene disorder. The evidence for this variant shows: no detailed phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory." The evidence for this variant shows: ClinVar entry and ClinGen Expert Panel report pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, BA1 applies at MAF ≥0.15%. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, BS1 applies at MAF 0.015–0.15%. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 applies to observation in healthy adults. The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, BS3 requires demonstration of normal function in transactivation assays. The evidence for this variant shows: loss of function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to general ACMG guidelines, BS4 applies when observed in ≥2 informative unaffected meioses. The evidence for this variant shows: no segregation data in unaffected individuals. 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 cause disease. The evidence for this variant shows: a truncating frameshift, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is observed in trans with a pathogenic variant for a dominant disorder. The evidence for this variant shows: no such observation. 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. The evidence for this variant shows: frameshift not in a simple repeat context. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, BP4 applies to benign computational evidence (REVEL <0.50 or SpliceAI ≤0.20). The evidence for this variant shows: frameshift variant not assessed by BP4. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant is found in a case with an alternative molecular basis for disease. The evidence for this variant shows: no such context. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports benign but evidence unavailable. The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for RUNX1, BP7 applies to synonymous/intronic variants with low splice impact and low conservation. The evidence for this variant shows: frameshift variant, not applicable. Therefore, this criterion is not applied.