RUNX1 c.296_298del, p.Cys99del
NM_001754.4:c.296_298del
Variant of Uncertain Significance (VUS)
Three Supporting-level pathogenic criteria (PM1, PM2, PM4) and no benign criteria result in a classification of Variant of Uncertain Significance due to insufficient evidence to meet pathogenic or benign thresholds.
ACMG/AMP Criteria Applied
PM1
PM2
PM4
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.296_298del
Protein Change
C99del
Location
Exon 4
(Exon 4 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001754.5
Genome Browser
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HGVS InputNM_001754:c.296_298del
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PVS1 rule is: "Very Strong Strength: Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects." The evidence for this variant shows an in-frame deletion of a single codon (C99del), which is not a null variant (nonsense, frameshift, canonical ±1/2 splice site, start codon loss, or exon deletion). Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PS1 rule is: "Strong Strength: 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 with the same cysteine 99 deletion. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the PS2 rule is: "Moderate Strength: For each proven de novo case give 0.5 points; for each assumed de novo case give 0.25 points; total 1.0 needed for Moderate." The evidence for this variant shows no confirmed de novo occurrences. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the PS3 rules are: "Strong Strength: Transactivation assays demonstrating altered function with secondary assay; Moderate Strength: transactivation OR ≥2 secondary assays; Supporting Strength: enhanced transactivation." The evidence for this variant shows no functional studies. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the PS4 rules are: "Strong Strength: ≥4 probands; Moderate Strength: 2–3 probands; Supporting Strength: 1 proband." The evidence for this variant shows no reported probands meeting RUNX1-phenotypic criteria. Therefore, this criterion is not applied.
PM1
PM1 (Supporting) Strength Modified
According to VCEP guidelines, the PM1 rule is: "Supporting Strength: Variant affecting one of the other amino acid residues 89–204 within the RHD." The evidence for this variant shows an in-frame deletion at codon 99, which lies within residues 89–204 of the RHD. Therefore, this criterion is applied at Supporting strength.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the PM2 rule is: "Supporting Strength: Variant must be completely absent from all population databases." The evidence for this variant shows it is not present in gnomAD or other control databases. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM3 rule applies to recessive disorders when in trans with a pathogenic variant. The evidence for this variant shows no trans observations with a pathogenic RUNX1 variant. Therefore, this criterion is not applied.
PM4
PM4 (Supporting) Strength Modified
According to VCEP guidelines, the PM4 rule is: "Supporting Strength: In-frame deletion/insertion impacting at least one of the other amino acid residues 89–204 within the RHD." The evidence for this variant shows an in-frame deletion at codon 99 within the RHD. Therefore, this criterion is applied at Supporting strength.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the PM5 rules apply to missense changes at residues with established pathogenic missense variants or to downstream nonsense/frameshift. This variant is an in-frame deletion, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the PM6 rule is: "Moderate Strength: de novo cases scoring to 1.0 points total for assumed/proven de novo." The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the PP1 rules are: "Supporting Strength: 3–4 informative meioses; Moderate Strength: 5–6 meioses; Strong Strength: ≥7 meioses." The evidence for this variant shows no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies when a missense variant is in a gene with low rate of benign missense variation. This variant is an in-frame deletion, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the PP3 rule is: "Supporting Strength: For missense variants, REVEL ≥0.88 or SpliceAI ≥0.38." The evidence for this variant shows a SpliceAI score of 0.04 and no REVEL score, and PP3 is for missense/intronic variants only. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies when phenotype is highly specific to a gene. No phenotype data are provided for this variant. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when multiple reputable sources report the variant as pathogenic. This variant is not present in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the BA1 rule is: "Stand Alone Strength: allele frequency ≥0.15% in general population datasets." 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 BS1 rule is: "Strong Strength: allele frequency between 0.015% and 0.15%." 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, BS2 applies when observed in a healthy adult for a dominant disorder. No such observations exist for this variant. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the BS3 rules require functional assays demonstrating normal function. No functional studies exist for this variant. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the BS4 rule is: "Strong Strength: applied when seen in ≥2 informative meioses inconsistent with pathogenic segregation." 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 genes where only truncating variants cause disease. This is an in-frame deletion. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when observed in trans with a pathogenic variant in a dominant disorder. No such observations exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame deletions in repetitive regions without known function. This variant is within the RHD domain, not a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the BP4 rule is: "Supporting Strength: For missense variants REVEL <0.50 and SpliceAI ≤0.20; for synonymous/intronic SpliceAI ≤0.20." This variant is an in-frame deletion. 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. No such cases exist. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when multiple reputable sources report the variant as benign. This variant is not reported in ClinVar. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the BP7 rule is: "Supporting Strength: for synonymous/intronic variants with SpliceAI ≤0.20 and phyloP ≤2.0." This variant is an in-frame deletion. Therefore, this criterion is not applied.