RUNX1 c.315_316insGT, p.Trp106ValfsTer17
NM_001754.4:c.315_316insGT
Pathogenic
The variant NM_001754.4:c.315_316insGT (W106Vfs*17) in RUNX1 is classified as Likely Pathogenic based on PVS1 (Very Strong), PM2 (Supporting), and PM5 (Supporting), consistent with loss-of-function mechanism and absence from population controls.
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.315_316insGT
Protein Change
W106Vfs*17
Location
Exon 4
(Exon 4 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 106 in gene RUNX1
Variant interpretation based on transcript NM_001754.5
Genome Browser
Loading genome browser...
HGVS InputNM_001754:c.315_316insGT
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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
No evidence of other pathogenic variants at position 106 in gene RUNX1
Functional Summary
The RUNX1 W106Vfs*17 variant is a truncating mutation in the RUNX1 gene, a tumor suppressor involved in hematopoietic differentiation. Functional evidence indicates that truncating mutations in RUNX1 inhibit its function, predisposing to hematologic malignancies such as leukemia, lymphomas, and myelodysplastic syndromes. This suggests a damaging effect of the variant.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
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 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: NM_001754.4:c.315_316insGT introduces a frameshift resulting in a premature termination codon in RUNX1, a gene where loss-of-function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it is a null variant consistent with the VCEP PVS1 rule.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 Strong strength is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: the c.315_316insGT frameshift does not result in the same amino acid change as any known pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point." The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 Strong strength is: "Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets PVS1. If variant meets PVS1_strong, either apply PS3_moderate or upgrade to PVS1." The evidence for this variant shows: it meets PVS1 and no specific transactivation assays were provided. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 Strong strength is: "≥ 4 probands meeting at least one of the RUNX1-phenotypic criteria." The evidence for this variant shows: no proband numbers or case series are reported. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 Supporting strength is: "Variant affecting one of the other amino acid residues 89-204 within the RHD." The evidence for this variant shows: NM_001754.4:c.315_316insGT is a frameshift, not a missense affecting a specific residue. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 at Supporting strength is: "Variant must be completely absent from all population databases." The evidence for this variant shows: it is absent from gnomAD and other large population datasets. Therefore, this criterion is applied at Supporting strength because the variant 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 autosomal recessive disorders." The evidence for this variant shows: RUNX1‐related disorders are dominant and no trans observations are reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 Moderate strength is: "In-frame deletion/insertion impacting at least one of the following amino acid residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204." The evidence for this variant shows: NM_001754.4:c.315_316insGT is a frameshift insertion, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM5 Supporting strength 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: the frameshift occurs at codon 106, downstream of c.98. Therefore, this criterion is applied at Supporting strength because it meets the specific VCEP PM5 rule.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 Supporting strength is: "3–4 meioses observed within one or across multiple families." The evidence for this variant shows: no family segregation data are available. Therefore, this criterion 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 variants are a common mechanism of disease." The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 Supporting strength is: "For missense variants: REVEL score ≥ 0.88; For missense, synonymous and intronic (intron 4-8) variants: SpliceAI ≥ 0.38." The evidence for this variant shows: it is a frameshift, not a missense or splicing prediction issue. Therefore, this criterion 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: no phenotype information is provided. Therefore, this criterion 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 or likely pathogenic without available evidence." The evidence for this variant shows: it is not found in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 Stand Alone strength is: "Minor allele frequency between 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles." The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 Strong strength is: "Minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles." The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a fully penetrant dominant disorder." The evidence for this variant shows: no such observations are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 Strong strength is: "Transactivation assays demonstrating normal transactivation (80–115% of wt) AND data from a secondary assay demonstrating normal function." The evidence for this variant shows: no normal functional assay results are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 Strong strength is: "Applied when seen in ≥ 2 informative meioses." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: it is itself a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 Supporting strength is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern." The evidence for this variant shows: no evidence of cis/trans observations with another pathogenic variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertions/deletions in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift insertion, not an in-frame event. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 Supporting strength is: "For missense variants: REVEL score < 0.50 AND SpliceAI ≤ 0.20; For synonymous and intronic variants: SpliceAI ≤ 0.20." The evidence for this variant shows: it is a frameshift, not amenable to these in silico metrics. Therefore, this criterion 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 alternate molecular basis is reported. Therefore, this criterion 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 or likely benign without evidence." The evidence for this variant shows: no such reports are available. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 Supporting strength is: "Applicable for synonymous and intronic variants with SpliceAI ≤ 0.20 AND phyloP ≤ 2.0." The evidence for this variant shows: it is a frameshift, not synonymous or intronic. Therefore, this criterion is not applied.