LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-15
Case ID: nm_005373_2_c_1544g_t
Framework: ACMG/AMP 2015
Variant classification summary

NM_005373.2:c.1544G>T

MPL  · NP_005364.1:p.(Trp515Leu)  · NM_005373.2
GRCh37: chr1:43815009 G>T  ·  GRCh38: chr1:43349338 G>T
Gene: MPL Transcript: NM_005373.2
Final call
Pathogenic
PS3 strong PS4 strong PM1 moderate PM2 supporting PM5 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
MPL
Transcript
NM_005373.2
Protein
NP_005364.1:p.(Trp515Leu)
gnomAD AF
1.2397857154369438e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 (Strong): the exact variant conferred cytokine-independent growth, constitutive JAK2/STAT/ERK/AKT activation, and lethal myeloproliferative disease in a murine transplant model.
2
PS4 (Strong): recurrently detected in affected myeloproliferative-neoplasm cohorts (4/45 JAK2V617F-negative myelofibrosis vs 0/270 controls, P=3.70e-4) against near-absence in population data.
3
PM1 (Moderate): codon 515 lies in the amphipathic KWQFP juxtamembrane motif, a mutational hotspot for activating MPL missense changes.
4
PM5 (Moderate): a different pathogenic missense change at the same residue, W515K, occurs in affected patients.
5
PM2 (Supporting): gnomAD v4.1 frequency 1.24e-5 (20/1,613,182 alleles) with 0 homozygotes, far below the 0.1% threshold.
6
Overall: Pathogenic under the generic ACMG/AMP 2015 '2 Strong' rule (PS3 + PS4), with no benign criterion met.
Final determination: Generic ACMG/AMP 2015 fallback: 2 Strong pathogenic criteria (PS3 strong + PS4 strong) are met with no conflicting benign evidence, which is a Pathogenic combination.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: a missense substitution is not a null variant, so no nonsense-mediated decay, truncation, or canonical splice mechanism applies.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: this nucleotide change is itself the variant that established MPL W515L, so no independent same-amino-acid comparator exists.
PMID:16834459 PMID:16868251 PMID:21326037
PS2 Not met Not met: no parental testing exists, and matched buccal DNA was negative for the variant, indicating an acquired somatic rather than de novo origin.
clinvar PMID:16834459 PMID:16868251 PMID:18769448 PMID:20113333 PMID:21326037 PMID:25741868 generic_acmg_combination_rules
PS3 Met Met (Strong): the exact variant conferred cytokine-independent growth and constitutive JAK2/STAT activation, and caused lethal myeloproliferative disease in a murine model.
PMID:16834459 PMID:18769448 PMID:28823277 PMID:16868251 PMID:25741868
PS4 Met Met (Strong): detected in 4/45 JAK2V617F-negative myelofibrosis patients versus 0/270 control samples (Fisher exact P=3.70e-4).
PMID:16834459 PMID:16868251 PMID:21326037 PMID:20113333 gnomad_v2 gnomad_v4
PM1 Met Met (Moderate): residue 515 lies in the amphipathic KWQFP juxtamembrane motif, a documented hotspot for activating MPL missense changes.
PMID:16868251 PMID:16834459 PMID:18769448 oncokb pm5_candidates
PM2 Met Met (Supporting): gnomAD v4.1 frequency 1.24e-5 (20/1,613,182 alleles, 0 homozygotes) is well below the 0.1% threshold.
gnomad_v4 gnomad_v2 oncokb PMID:16834459 PMID:16868251 PMID:21326037 PMID:20113333 PMID:25741868 generic_acmg_combination_rules
PM3 Not met Not met: no affected individual carries this variant in trans with a second pathogenic MPL allele, and it is characterised as a somatic mutation.
clinvar PMID:16834459 PMID:16868251 PMID:20113333 PMID:21326037 PMID:25741868
PM4 N/A Not applicable: a missense substitution does not change protein length, so no in-frame indel or stop-loss mechanism applies.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Met Met (Moderate): a different pathogenic missense change at the same residue, W515K, was found in 5 of 1182 screened patients.
PMID:16868251 PMID:20113333 PMID:21326037 pm5_candidates
PM6 Not met Not met: no de novo assertion exists, and matched buccal DNA was negative for the substitution, consistent with an acquired somatic event.
clinvar PMID:16834459 PMID:16868251 PMID:20113333 PMID:21326037 PMID:25741868 generic_acmg_combination_rules
PP1 Not assessed Not assessed: no pedigree or affected-relative genotypes were available, so co-segregation with disease could not be evaluated.
clinvar PMID:16868251 PMID:25741868 generic_acmg_combination_rules
PP2 Not assessed Not assessed: missense change is a known MPL disease mechanism, but no gene-level missense constraint metric was available.
PMID:16868251 PMID:16834459 pvs1_gene_context final_classification_framework
PP3 Not met Not met: REVEL 0.328 falls inside the 0.250-0.750 gray zone, so no missense computational support applies.
revel
PP4 Not assessed Not assessed: no proband phenotype, diagnosis, or laboratory findings were available to compare with MPL disease specificity.
PP5 Not met Not met: ClinVar variation 14164 has no expert-panel submission, only single-submitter laboratory assertions.
clinvar
BA1 Not met Not met: gnomAD v4.1 frequency 1.24e-5 (0.00124%) is roughly four orders of magnitude below the 5% stand-alone threshold.
gnomad_v4 gnomad_v2 PMID:25741868 generic_acmg_combination_rules
BS1 Not met Not met: gnomAD v4.1 grpmax FAF 1.77e-5 (0.0018%) is far below the 0.3% threshold expected for this disorder.
gnomad_v4 gnomad_v2 PMID:16868251 PMID:20113333 PMID:25741868 generic_acmg_combination_rules
BS2 Not met Not met: 0 homozygotes in gnomAD (0/1,613,182 alleles), and no MPL515 mutation was found among 64 healthy controls.
gnomad_v4 gnomad_v2 clinvar PMID:16834459 PMID:16868251 PMID:21326037 PMID:25741868
BS3 Not met Not met: no well-established study shows absence of effect, while exact-variant assays demonstrate constitutive receptor activation and TPO hypersensitivity.
PMID:20113333 PMID:16834459 PMID:18769448 PMID:25741868
BS4 Not assessed Not assessed: no pedigree or affected-relative genotypes were available, so lack of segregation with disease could not be evaluated.
clinvar PMID:16868251 PMID:25741868 generic_acmg_combination_rules
BP1 Not met Not met: missense change is an established MPL disease mechanism, including activating W515L and W515K and the familial S505N allele.
PMID:16868251 PMID:16834459 oncokb
BP2 Not met Not met: no report places this variant in cis with a pathogenic MPL allele, and no allelic phase data exist.
clinvar PMID:16834459 PMID:16868251 PMID:20113333 PMID:21326037 PMID:25741868
BP3 N/A Not applicable: a missense substitution does not create an in-frame change within a repetitive region.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL 0.328 sits inside the 0.250-0.750 gray zone, so no computational benign support applies.
revel
BP5 Not assessed Not assessed: no proband genotype or phenotype was available to establish an alternative molecular basis for disease.
PMID:16868251
BP6 Not met Not met: ClinVar variation 14164 carries no expert-panel submission and no benign or likely benign assertion.
clinvar
BP7 N/A Not applicable: BP7 covers silent variants, whereas this missense substitution alters the encoded protein sequence.
generic_acmg_combination_rules
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.