RUNX1 c.312_313dup, p.His105ArgfsTer18
NM_001754.4:c.312_313dup
Pathogenic
This frameshift variant in RUNX1 meets VCEP PVS1 Very Strong for null variants and two supporting criteria (PM2, PM5), yielding a final classification of Pathogenic based on established gene-specific and 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.312_313dup
Protein Change
H105Rfs*18
Location
Exon 4
(Exon 4 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 105: H105Q, H105P
Variant interpretation based on transcript NM_001754.5
Genome Browser
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HGVS InputNM_001754:c.312_313dup
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
ClinVar reports other pathogenic variants at position 105: H105Q, H105P
PM5 criterion applied.
Functional Summary
The RUNX1 H105Rfs*18 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, 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: a frameshift (c.312_313dup; H105Rfs*18) leading to a premature stop codon and loss of function in RUNX1, a gene where LOF is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP decision tree for null variants not in the last exon.
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: it is a frameshift, not a same amino acid missense change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is de novo occurrence with confirmed paternity/maternity. The evidence for this variant shows: no de novo data available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 Strong is: "Not applicable if variant meets PVS1." The evidence for this variant shows: it meets PVS1 Very Strong. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Increased prevalence in affected individuals compared to controls." The evidence for this variant shows: no case-control or proband count data. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate if affecting one of specified critical residues in the RHD domain." The evidence for this variant shows: it is a frameshift, not a missense affecting those residues. 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 for this variant shows: absent from gnomAD, ExAC, 1000G, and ESP. Therefore, PM2 is applied at Supporting strength because it is completely absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: RUNX1 disease is dominant and no trans data. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a frameshift causing truncation, not an in-frame event. 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 for this variant shows: it is a frameshift at c.312 (downstream of c.98). Therefore, PM5 is applied at Supporting strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo occurrence without confirmation of paternity/maternity." The evidence for this variant shows: no de novo data. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common disease mechanism." The evidence for this variant shows: it is a frameshift. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting for missense variants with REVEL ≥0.88 or SpliceAI ≥0.38." The evidence for this variant shows: it is a frameshift. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: phenotype data not provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency ≥0.0015 in general population." The evidence for this variant shows: absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency between 0.00015 and 0.0015 in general population." The evidence for this variant shows: absent from population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy adult individuals at an expected frequency for a dominant disorder." The evidence for this variant shows: no healthy individual observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 Strong is: "Transactivation assays demonstrating normal function." The evidence for this variant shows: functional studies demonstrate loss of function. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LOF causes disease." The evidence for this variant shows: it is a LOF frameshift. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis with a pathogenic variant or in trans for dominant gene." The evidence for this variant shows: no such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in repetitive region without known function." The evidence for this variant shows: it is frameshift, not in-frame. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting for missense variants with REVEL <0.50 and SpliceAI ≤0.20." The evidence for this variant shows: it is a frameshift. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such context. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without evidence." The evidence for this variant shows: no such reports. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant with SpliceAI ≤0.20 and low conservation." The evidence for this variant shows: it is a frameshift. Therefore, BP7 is not applied.