RUNX1 c.1176G>A, p.Gln392=
NM_001754.4:c.1176G>A
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Likely Benign
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.1176G>A
Protein Change
Q392=
Location
Exon 9
(Exon 9 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001754.5
Clinical Evidence
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 170092
Alt: 0
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0%, 0/170092 alleles, homozygotes = 0) but does not appear at a higher frequency in any of the selected populations. The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Likely benign by ClinGen Myeloid Malignancy Variant Curation Expert Panel expert panel.
Expert Panel Reviews
Likely benign
ClinGen Myeloid Malignancy Variant Curation Expert Panel
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 Studies
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.77
VCEP Guidelines
Applied ACMG/AMP Criteria
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 variant is a synonymous change (no stop gain, frameshift, or canonical splice site alteration) and SpliceAI predicts no impact on splicing. Therefore, PVS1 is not applied.
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." This variant is synonymous and does not change the amino acid. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, PS2 pertains to de novo observations; no de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to VCEP guidelines, PS3 (Strong) requires well-established functional studies demonstrating altered function. No functional studies have been conducted for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, PS4 (Strong) requires ≥4 probands meeting RUNX1-phenotypic criteria. No proband data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, PM1 (Moderate) applies to missense variants affecting key residues within the RHD (amino acids 89–204). This variant is synonymous at residue 392, outside the RHD. 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." This variant is absent from gnomAD (MAF = 0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM3 applies to variants detected in trans with a pathogenic variant for a recessive disorder. RUNX1 disorders are dominant and no in trans data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels). This is a synonymous SNV with no length change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues with known pathogenic missense variants. This variant is synonymous. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines, PM6 pertains to assumed de novo cases; no de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, PP1 requires segregation data in affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation. This is a synonymous variant. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, PP3 (Supporting) for synonymous variants would require SpliceAI ≥0.38. SpliceAI predicts no impact (score = 0). Therefore, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP4 applies when phenotype is highly specific for gene. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source classifies variant as pathogenic without evidence; here no such source reports pathogenic. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, BA1 (Stand Alone) requires MAF ≥0.15% in any population. This variant is absent (MAF = 0%). Therefore, BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, BS1 (Strong) requires MAF between 0.015% and 0.15%. This variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS2 requires observation in healthy adults inconsistent with disease penetrance. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, BS3 (Strong) requires normal functional studies. No functional studies are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS4 requires non-segregation in multiple informative 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 is synonymous. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is observed in trans with a dominant pathogenic variant or in cis with a pathogenic variant. No such data are available. 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 SNV. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: For synonymous and intronic variants: SpliceAI ≤ 0.20." SpliceAI predicts no splicing impact (score = 0). Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a gene for which another etiology is known. Not applicable here. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." ClinVar and the ClinGen Myeloid Malignancy VCEP report this variant as Likely benign. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: BP7 is applicable for synonymous and intronic variants with SpliceAI ≤ 0.20 AND phyloP100 way ≤2.0." SpliceAI = 0 and conservation metrics indicate low conservation. Therefore, BP7 is applied at Supporting strength.