MPL c.1543_1544delinsAA, p.Trp515Lys
NM_005373.2:c.1543_1544delinsAA
COSM19193
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Not Classified
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
49 occurrences
PM1 Criterion Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
MPL
Transcript
NM_005373.3
MANE Select
Total Exons
12
Strand
Forward (+)
Reference Sequence
NC_000001.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_005373.1 | Alternative | 12 exons | Forward |
| NM_005373.2 | RefSeq Select | 12 exons | Forward |
Variant Details
HGVS Notation
NM_005373.2:c.1543_1544delinsAA
Protein Change
W515K
Location
Exon 10
(Exon 10 of 12)
5'
Exon Structure (12 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 515: W515L
Alternate Identifiers
COSM19193
Variant interpretation based on transcript NM_005373.3
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Not Classified
Publications
0 publications
Clinical Statement
Present in ClinVar, however no clinical evidence available for this variant.
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 515: W515L
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
The MPL W515K variant has been functionally characterized as oncogenic. It is located in the amphipathic domain of the MPL protein and has been shown to be activating. Experimental studies in murine B cells and Ba/F3 cells demonstrated increased JAK2-STAT5 signaling, cytokine-independent proliferation, and hypersensitivity to thrombopoietin compared to wildtype MPL. Additionally, endogenous expression in patient-derived CD34+ cells resulted in spontaneous megakaryocytic growth and enhanced proliferative response to growth factors.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
polyphen_prediction: benign
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function is a known mechanism of disease". The evidence for this variant shows a missense change rather than a predicted loss-of-function. Therefore, this criterion is not applied.
PS1
PS1 (Strong)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows c.1543_1544delinsAA results in the W515K amino acid change, which is a well-established pathogenic MPL variant via a different nucleotide mechanism. Therefore, this criterion is applied at Strong strength.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". There are no data on de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows in vitro and in vivo studies demonstrating oncogenic activation (increased JAK2-STAT5 signaling, cytokine-independent proliferation, hypersensitivity to thrombopoietin, spontaneous megakaryocytic growth). Therefore, this criterion is applied at Strong strength.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". There are no case–control or statistical prevalence data provided. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows W515 lies in the MPL amphipathic domain and is a known mutational hotspot in myeloproliferative neoplasms. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows it is absent from population databases including gnomAD. Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". This is a dominantly acting oncogenic variant, and no trans allelic data are relevant. Therefore, this criterion 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 deletions/insertions or stop-loss variants". This variant does not change protein length but results in a missense substitution. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". Although W515 is a pathogenic hotspot, this exact amino acid change is already accounted for by PS1, which supersedes PM5. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". There are no data on de novo status. Therefore, this criterion 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". Segregation data are not 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 a low rate of benign missense variation and where missense variants are a common mechanism of disease". There is insufficient evidence regarding the overall missense tolerance of MPL for this criterion. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product". Computational predictions are mixed and largely benign, so no deleterious signal is supported. 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 highly specific for a disease with a single genetic etiology". No phenotype or family history data are 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, but without accessible evidence". No such report is available. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The variant is absent from population databases, so BA1 does not apply. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The variant 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 healthy individuals with full penetrance expected at an early age". No such observations exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". Functional studies demonstrate a damaging activating effect, so BS3 is contradicted. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". No segregation data are provided. 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 a gene where only loss-of-function causes disease". MPL gain-of-function missense variants cause disease. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". No such data exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". This variant is not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows mixed in silico predictions and SpliceAI predicts no splicing impact (max score 0.06). Therefore, this criterion is applied at Supporting strength.
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". No such alternate diagnosis 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, but without accessible evidence". No such report is available. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". This is a missense variant. Therefore, this criterion is not applied.