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LYFE SCIENCES
Project: HERA
NM_005373.2:c.1544G>T
p.Trp515Leu  ·  MPL
ACMG/AMP
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Classification rationale
1

The MPL c.1544G>T (p.Trp515Leu; p.W515L) variant has been reported in somatic myeloproliferative neoplasms and is listed in ClinVar with one Pathogenic submission and one Uncertain significance submission.

clinvar ↗ PMID:16834459 ↗ PMID:16868251 ↗ PMID:20113333 ↗ PMID:21326037 ↗
2

This variant is rare in population databases, with gnomAD v2.1 allele frequency 7.98378e-06 (0.00080%, 2/250508) and gnomAD v4.1 allele frequency 1.23979e-05 (0.00124%, 20/1613182), both below the 0.1% PM2 threshold.

gnomad_v2 ↗ gnomad_v4 ↗
3

Available functional evidence supports an abnormal activating effect, as p.W515L is described as an activating MPL variant and OncoKB classifies it as oncogenic with gain-of-function activity.

oncokb ↗ PMID:16834459 ↗ PMID:28823277 ↗
4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 7.98378e-06; MAF= 0.00080%, 2/250508 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15612e-05; MAF= 0.00616%, 1/16244 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.23979e-05; MAF= 0.00124%, 20/1613182 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 6.683e-05; MAF= 0.00668%, 3/44890 alleles, homozygotes = 0); grpmax FAF= 1.772e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Oncogenic
OncoKB classifies this variant as Oncogenic; biological effect: Gain-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV65243776, n = 277 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueW515
Hotspots ↗