Classification rationale

PM2PM4 VUS

MPL c.1494_1495insGTGATCGCTCTG in_frame_indel_unknown · exon 10

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1. PM4 moderate: the in-frame insertion adds four amino acids at p.Leu498_His499 in the MPL transmembrane region.

PM2 + PM4 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_005373.2 · variants mapped to exon structure

MPL NM_005373.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, consistent with the PM2 allele-frequency threshold of <=0.0001.

The governing framework record reports no applicable CSPEC/VCEP or gene-specific framework; generic ACMG/AMP rules therefore apply.The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada; no population allele count or frequency was reported.The generic ClinGen SVI PM2 recommendation uses an allele-frequency threshold of <=0.0001 and assigns PM2 supporting strength (ClinGen SVI 2020, PMID:25741868).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PM4 moderate Pathogenic

Met, moderate: the in-frame insertion adds four amino acids at p.Leu498_His499 within a non-repetitive transmembrane-region sequence.

The normalized transcript annotation is NM_005373.2:c.1494_1495insGTGATCGCTCTG, producing NP_005364.1:p.(Leu498_His499insValIleAlaLeu).The inserted sequence is 12 nucleotides, corresponding to a four-amino-acid in-frame insertion, so the protein length changes without a frameshift or premature stop.Variant Validator places the change in coding exon 10, and the predicted protein sequence places p.Leu498_His499 within the hydrophobic transmembrane-region sequence rather than a repetitive low-complexity segment.

Assessed · not applied · 6 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no proband-parent testing or documented de novo observation is available.

PS3 Not assessed: no validated MPL functional assay, controls, or quantitative result was available for this in-frame insertion.

PS4 Not assessed: no affected-case series, control comparison, odds ratio, or other case-control enrichment measure was reported for this exact variant.

PM3 Not assessed: no affected-proband observation or phase-resolved pathogenic variant in trans is documented for this variant.

PM6 Not assessed: no apparently de novo observation with unconfirmed parental status is documented.

PP1 Not assessed: no affected relatives, informative meioses, or segregation counts are documented.

PP4 Not assessed: no individual clinical phenotype or disease-specific feature set was provided to evaluate phenotype specificity for PP4.

PP5 Not met: the exact variant is absent from ClinVar, with no expert-panel Pathogenic or Likely pathogenic classification available.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having an allele frequency >=0.05 required for BA1.

BS1 Not met: gnomAD v2.1 and v4.1 show no observations, so the allele frequency does not reach the generic BS1 threshold of >=0.01.

BS2 Not met: gnomAD v2.1 and v4.1 report no carriers, providing no evidence of healthy adult homozygotes for BS2.

BS3 Not assessed: no validated MPL assay demonstrated preserved function for this in-frame insertion.

BS4 Not assessed: no reliable non-segregation observations in informative unaffected relatives are documented.

BP2 Not assessed: no documented pathogenic partner variant or cis/trans phase information is available for this variant.

BP3 Not met: p.Leu498_His499 is a four-amino-acid insertion in the specific MPL transmembrane region, not a functionless repetitive protein segment.

BP5 Not assessed: no patient-level alternate molecular diagnosis or evidence that another pathogenic variant explains the phenotype was provided.

BP6 Not met: the exact variant is absent from ClinVar, with no expert-panel Benign or Likely benign classification available.

N/A · 9 PVS1 · PS1 · PM1 · PM5 · PP2 · PP3 · BP1 · BP4 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MPL, a transmembrane protein receptor, is frequently mutated in myeloproliferative neoplasms including essential thrombocytosis and myelofibrosis.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV65244673, n = 4 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Check your email

Reset your password

Enter an access code

Your allowance