RUNX1 c.1064dup, p.Tyr355Ter
NM_001754.4:c.1064dup
COSMIC ID: COSM7449607
Pathogenic
This RUNX1 c.1064dup (p.Y355*) truncating variant results in loss of function. It meets PVS1 at Very Strong, PM2 at Supporting, and PM5 at Supporting, consistent with likely pathogenic classification under VCEP-modified ACMG guidelines.
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.1064dup
Protein Change
Y355*
Location
Exon 9
(Exon 9 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM7449607
Variant interpretation based on transcript NM_001754.5
Genome Browser
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HGVS InputNM_001754:c.1064dup
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
Functional Summary
The RUNX1 Y355* variant is a truncating mutation in a tumor suppressor gene, likely resulting in loss of function. Functional evidence indicates that such truncating mutations in RUNX1 inhibit its role in hematopoietic differentiation, predisposing to hematologic malignancies.
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 frameshift/nonsense truncating mutation (Y355*) in RUNX1, a gene where loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is predicted to result in loss of function in a gene with LOF pathogenicity.
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 no previously established pathogenic variant causing Y355*. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Moderate/Supporting de novo evidence based on points for proven or assumed cases." The evidence for this variant provides no parental testing or de novo confirmation. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, "PS3 is not applicable if variant meets PVS1." The evidence shows the variant meets PVS1. Therefore, PS3 is not applied despite functional data because PVS1 supersedes PS3 in VCEP RUNX1 rules.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 Strong is: "≥4 probands meeting at least one of the RUNX1-phenotypic criteria." The evidence presents no case counts or phenotypic cohort data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 Moderate is: "Variant affecting one of the specified RHD residues (R107, K110, …, R204)." The evidence shows Y355* lies outside the RHD region (residues 89–204). Therefore, PM1 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 shows the variant is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength.
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." There is no evidence of a second allele or recessive inheritance for this variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 applies to in-frame insertions/deletions. This variant is a frameshift duplication. Therefore, PM4 is not applied.
PM5
PM5 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM5 Supporting is: "PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 in transcript NM_001754.4." The evidence shows this Y355* truncating variant is at c.1064 (downstream of c.98). Therefore, PM5 is applied at Supporting strength.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo cases scored similar to PS2." No de novo or assumed de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 Supporting is: "3–4 meioses observed with co-segregation." No family segregation data are provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a truncating duplication. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 Supporting is: "REVEL ≥0.88 for missense or SpliceAI ≥0.38 for splicing." The variant is truncating and SpliceAI score is 0, not applicable. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies when phenotype is highly specific and consistent. No detailed clinical phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies based on reputable source assertions without available evidence. No such assertions exist. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies to variants with MAF ≥0.15%. The variant is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies to variants with MAF between 0.015%–0.15%. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 applies when variant is observed in healthy adult individuals. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when functional studies demonstrate normal function. Available studies show loss of function. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 applies when variant does not segregate with disease in multiple meioses. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. This variant is truncating. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to variants observed in trans with a pathogenic variant in dominant genes. No such data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a frameshift duplication. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 Supporting is: "REVEL <0.50 and/or SpliceAI ≤0.20 for missense/synonymous/intronic." The variant is truncating and SpliceAI is 0 but BP4 does not apply to truncating variants. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant is found in trans with a pathogenic variant for a fully penetrant dominant gene. No such data exist. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies based on other source assertions of benign. No such assertions exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous/intronic variants with SpliceAI ≤0.20 and low conservation. This variant is truncating. Therefore, BP7 is not applied.