Variant classification summary

NM_005373.2:c.1513A>T

MPL · NP_005364.1:p.(Ser505Cys) · NM_005373.2

GRCh37: chr1:43814978 A>T · GRCh38: chr1:43349307 A>T

Gene: MPL Transcript: NM_005373.2

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting BP4 supporting

Variant details

Gene

MPL

Transcript

NM_005373.2

Protein

NP_005364.1:p.(Ser505Cys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: S505C enhanced W515R/L-driven MPL signaling and proliferation and formed ligand-independent dimers, but was inactive alone.

2

PM1 moderate: Ser505 lies in MPL's exon-10 transmembrane mutational hotspot.

3

PM2 supporting: the variant is absent from gnomAD and meets the generic rarity threshold.

4

BP4 supporting: SpliceAI maximum delta 0.019 predicts minimal splice impact.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one moderate and two supporting pathogenic criteria combined with one supporting benign criterion is a conflicting combination that results in VUS.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_005373.2:c.1513A>T in MPL is a missense substitution predicted to produce NP_005364.1:p.(Ser505Cys). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: the exact p.Ser505Cys change is reported somatically, but no established pathogenic same-amino-acid comparator is available.	PMID:34845187 PMID:31697803 clinvar
PS2	Not assessed	Not assessed: no confirmed proband de novo result with genotyped biological parents is documented for NM_005373.2:c.1513A>T.
PS3	Met	Met at supporting: S505C increased autonomous STAT5 signaling and proliferation with W515R/L and formed ligand-independent dimers, but was inactive alone.	PMID:34845187 PMID:31697803 generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control cohort or enrichment statistic is available to establish PS4 for MPL p.Ser505Cys.	PMID:34845187 PMID:31697803
PM1	Met	Met at moderate strength: Ser505 lies in MPL's exon-10 transmembrane hotspot, a critical region for disease-associated receptor activation.	PMID:31697803
PM2	Met	Met at supporting: gnomAD observed frequency is 0 because the variant is absent, satisfying the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	N/A	Not applicable: no affected-proband germline evidence, trans-phase observation, or established recessive MPL disorder is documented.	PMID:34845187 PMID:31697803
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_005373.2:c.1513A>T in MPL is a missense substitution predicted to produce NP_005364.1:p.(Ser505Cys). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no distinct established pathogenic missense substitution at MPL residue 505 is documented; functional scan results do not establish PM5.	PMID:34845187 PMID:31697803
PM6	Not assessed	Not assessed: no suspected de novo occurrence with documented phenotype and parental relationship information is available for this variant.
PP1	Not assessed	Not assessed: zero informative affected-relative meioses or phenotype-consistent familial transmissions are documented for this variant.
PP2	Not assessed	Not assessed: no applicable gene-level evidence establishes MPL's required predominant missense mechanism and low benign missense rate for PP2.
PP3	Not met	Not met: REVEL 0.422 and SpliceAI maximum delta 0.019 are both below their PP3 supporting thresholds of 0.644 and 0.2, respectively.	revel spliceai
PP4	Not assessed	Not assessed: essential thrombocythemia is not sufficiently specific, and the reported patient also carried an MPL W515 driver mutation.	PMID:34845187 PMID:31697803
PP5	Not met	Not met: the exact variant is absent from ClinVar and has no expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: the variant was absent from gnomAD, corresponding to an observed frequency of 0, below the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: the variant was absent from gnomAD, with observed frequency 0 below the >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not assessed	Not assessed: gnomAD reports no carriers or homozygotes, so there is no unaffected-adult observation to support BS2.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: S505C was inactive alone but enhanced W515R/L STAT5 signaling and proliferation and formed ligand-independent MPL dimers.	PMID:34845187 PMID:31697803
BS4	Not assessed	Not assessed: no tested unaffected relatives or informative non-segregation observations are documented for NM_005373.2:c.1513A>T.
BP1	Not assessed	Not assessed: the available MPL evidence does not establish a truncating-predominant germline disease mechanism required for BP1.
BP2	N/A	Not applicable: S505C was observed somatically in cis with activating W515 variants, not in a qualifying inherited BP2 phase context.	PMID:34845187 PMID:31697803
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_005373.2:c.1513A>T in MPL is a missense substitution predicted to produce NP_005364.1:p.(Ser505Cys). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: SpliceAI maximum delta 0.019 meets the <=0.1 BP4 threshold, despite REVEL 0.422 exceeding its <=0.29 threshold.	spliceai revel
BP5	Not assessed	Not assessed: co-occurring MPL W515 mutations provide an alternative basis, but S505C may enhance their activity and is not shown to be irrelevant.	PMID:34845187 PMID:31697803
BP6	Not met	Not met: the exact variant is absent from ClinVar and has no expert-panel Benign or Likely benign classification.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005373.2:c.1513A>T in MPL is a missense substitution predicted to produce NP_005364.1:p.(Ser505Cys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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