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

Likely Pathogenic

PS3 PM1 PM2

Variant details

Gene

MPL

Transcript

NM_005373.2

Protein

NP_005364.1:p.(Trp515Leu)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Not met	This is a missense variant, and the generic PVS1 framework indicates that it does not fall within the null-variant categories used for PVS1 application.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified here showing a different nucleotide change that results in the same amino acid substitution with an established pathogenic classification.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified.
PS3	Met	Functional evidence supports a damaging effect. This variant is described as an activating MPL mutation in the literature, and OncoKB classifies p.W515L as oncogenic with gain-of-function activity, which is consistent with an abnormal functional effect relevant to disease.	oncokb PMID:16834459 PMID:28823277
PS4	Not assessed	This variant has been reported in affected myeloproliferative neoplasm cohorts, but the available evidence does not provide a germline case-control comparison sufficient to determine whether the prevalence in affected individuals is significantly increased over controls for ACMG PS4.	PMID:16834459 PMID:16868251 PMID:20113333 PMID:21326037
PM1	Met	This missense variant affects MPL codon Trp515, a recurrent activating site associated with myeloproliferative neoplasms. The variant has recurrent somatic observations and variant-specific oncogenic gain-of-function annotation, supporting location in a critical functional region.	oncokb PMID:16834459 PMID:16868251
PM2	Met	Population frequency is very low. In gnomAD v2.1 the allele frequency is 7.98378e-06 (0.00080%, 2/250508), and in gnomAD v4.1 the allele frequency is 1.23979e-05 (0.00124%, 20/1613182), with highest observed population frequency 6.683e-05 (0.00668%, East Asian) and grpmax FAF 1.772e-05; these values are all below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	No recessive context with confirmed trans observations was identified for this variant.
PM4	N/A	This is a missense substitution and does not cause a protein length change.
PM5	Not assessed	Other potentially relevant missense changes at codon 515 are mentioned in the literature, but a curated same-residue pathogenic comparison suitable for ACMG PM5 was not established here.	PMID:20113333
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified.
PP1	Not assessed	No segregation data were identified.
PP2	Not assessed	Available evidence does not establish a gene-specific missense mechanism or constraint pattern sufficient to apply PP2.
PP3	Not met	Computational evidence does not independently support a splice-disrupting effect. SpliceAI shows a maximum delta score of 0.03, which is below commonly used splice concern thresholds.	spliceai
PP4	Not assessed	No individual-level phenotype data were identified that would show a highly specific MPL-related presentation for this variant.
PP5	N/A	Assertion-based evidence from external classifications is not used as independent support under current ACMG/AMP practice.	clinvar
BA1	Not met	Population frequency is below the benign stand-alone threshold. The highest observed gnomAD v4.1 population frequency is 6.683e-05 (0.00668%), which is below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Population frequency is below the benign strong threshold. The highest observed gnomAD v4.1 population frequency is 6.683e-05 (0.00668%), which is below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	The variant is present at very low frequency in population databases, but those observations do not establish occurrence in well-phenotyped healthy individuals sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not met	Available functional evidence does not support a benign effect. Instead, the identified studies and curated oncology annotation are consistent with an activating effect.	oncokb PMID:16834459 PMID:28823277
BS4	Not assessed	No nonsegregation data were identified.
BP1	N/A	Available evidence does not support using BP1 for this missense variant.
BP2	Not assessed	No phase data with another pathogenic variant were identified.
BP3	Not assessed	No evidence was identified showing that this variant lies in a repetitive region without known function.
BP4	Not met	Computational evidence does not support a benign splice effect. SpliceAI predicts no significant splice impact, but that finding alone is not sufficient to support BP4 for this missense variant.	spliceai
BP5	Not assessed	No alternate molecular explanation for the observed disease was identified.
BP6	N/A	Assertion-based evidence from external classifications is not used as independent benign support under current ACMG/AMP practice.	clinvar
BP7	N/A	This criterion is not applicable because the variant is missense rather than synonymous or intronic outside splice-impact positions.

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