RUNX1 c.296_298del, p.Cys99del
NM_001754.4:c.296_298del
Variant of Uncertain Significance (VUS)
Three supporting pathogenic criteria (PM1_supporting, PM2_supporting, PM4_supporting) are met, which is insufficient for a Likely Pathogenic classification and no benign criteria are met. Thus, the variant remains a VUS.
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 rule for PVS1 is: "Very Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects." The evidence for this variant shows it is an in-frame single amino acid deletion (C99del), not a null frameshift or canonical ±1/2 splice site. Therefore, this criterion is not applied because the variant does not meet the definition of a loss-of-function null variant.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 Strong is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no prior pathogenic variant resulting in C99del reported. Therefore, this criterion is not applied because there is no known pathogenic variant with the identical amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 Moderate is: "Phenotype consistent with gene but not highly specific and high genetic heterogeneity. For each proven de novo case give 0.5 points…Moderate = 1.0 points total." The evidence for this variant shows no de novo status has been established. Therefore, this criterion is not applied due to absence of de novo data.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 Strong is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows no functional studies have been performed. Therefore, this criterion is not applied because required functional data are missing.
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 for this variant shows no proband data. Therefore, this criterion is not applied due to lack of case data.
PM1
PM1 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM1 Supporting is: "Variant affecting one of the other amino acid residues 89-204 within the RHD." The evidence for this variant shows deletion of C99, which lies between residues 89 and 204 in the Runt Homology Domain. Therefore, this criterion is applied at Supporting strength because the variant affects a non-hotspot residue within the critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 Supporting is: "Variant must be completely absent from all population databases." The evidence for this variant shows it is not present in gnomAD or other control datasets. Therefore, this criterion is applied at Supporting strength due to absence from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 Moderate is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows no information on trans phase with another variant. Therefore, this criterion is not applied.
PM4
PM4 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM4 Supporting is: "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 of codon 99, which is within residues 89-204. Therefore, this criterion is applied at Supporting strength because it is an in-frame deletion in the domain outside the specific hotspot residues.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 Moderate is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows it is an in-frame deletion, not a missense change at a residue with known pathogenic missense variants. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 Moderate is: "Phenotype consistent with gene…for each assumed de novo case give 0.25 points…Moderate = 1.0 points total." The evidence for this variant shows no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 Supporting is: "3 or 4 meioses observed within one or across multiple families." The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 Supporting is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows it is an in-frame deletion, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 Supporting is: "For missense variants: REVEL ≥ 0.88 or SpliceAI ≥ 0.38…" The evidence for this variant shows it is an in-frame deletion and SpliceAI score is 0.04. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 Supporting 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 phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 Supporting is: "Reputable source recently reports variant as pathogenic." The evidence for this variant shows no ClinVar or other report. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 Stand Alone is: "Minor allele frequency ≥ 0.15% in any general population dataset." The evidence for this variant shows it is absent from all population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 Strong is: "Minor allele frequency between 0.015% and 0.15% in any general population dataset." 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 Strong is: "Observed in a healthy adult individual for a dominant disorder with full penetrance." The evidence for this variant shows no healthy adult observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 Strong is: "Transactivation assays demonstrating normal function AND secondary assay normal." The evidence for this variant shows no functional assays. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 Strong 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 Supporting is: "Missense variant in a gene where only loss-of-function causes disease." The evidence for this variant shows an in-frame deletion. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 Supporting is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene." 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, the rule for BP3 Supporting is: "In-frame deletion in a repetitive region without known function." The evidence for this variant shows no repetitive region context. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 Supporting is: "For missense variants REVEL < 0.50 and SpliceAI ≤ 0.20." The evidence for this variant shows an in-frame deletion. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 Supporting is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows no alternate diagnosis. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 Supporting is: "Reputable source reports variant as benign." The evidence for this variant shows no such report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 Supporting is: "Synonymous or intronic variant with SpliceAI ≤ 0.20 and phyloP100way ≤ 2.0." The evidence for this variant shows it is an in-frame coding deletion. Therefore, this criterion is not applied.