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NM_005373.2:c.1494_1495insGTGATCGCTCTG
p.Leu498_His499insValIleAlaLeu · MPL
ACMG/AMP
0%
complete
Final classification
VUS
PM2PM4BP4
MPL
c.1494_1495insGTGATCGCTCTG
p.Leu498_His499insValIleAlaLeu
in_frame_indel_unknown · exon 10
Gene context NCBI Gene ↗ OncoKB ↗

MPL encodes the thrombopoietin receptor, a cell-surface protein that helps control the production of megakaryocytes and platelets through JAK-STAT and related signaling pathways. Changes that increase or reduce MPL activity can cause inherited platelet disorders, including abnormally high platelet counts or severe congenital thrombocytopenia with bone marrow failure. MPL also acts as an oncogene: activating changes are associated with myeloproliferative neoplasms such as essential thrombocythemia and myelofibrosis.

This variant

MPL encodes the thrombopoietin receptor governing megakaryocyte and platelet production, and altered receptor activity causes both congenital amegakaryocytic thrombocytopenia and myeloproliferative neoplasms such as essential thrombocythemia. This in-frame transmembrane insertion is absent from population databases but has no functional or clinical data establishing its direction of effect, so it cannot be assigned to either the loss-of-function or the activating disease mechanism. It is therefore reported as a variant of uncertain significance, pending functional or family evidence.

Transcript
NM_005373.2
HGVS · transcript:coding
NM_005373.2:c.1494_1495insGTGATCGCTCTG
GRCh38
chr1:43349281 C>CCGCTCTGGTGAT
GRCh37
chr1:43814952 C>CCGCTCTGGTGAT
VUS: 1 moderate plus 1 supporting pathogenic criterion against 1 supporting benign criterion reaches no ACMG/AMP 2015 combination threshold.
Classification rationale
PM2PM4 BP4 VUS
MPL c.1494_1495insGTGATCGCTCTG in_frame_indel_unknown · exon 10

PM2 (Supporting): absent from gnomAD v2.1, v4.1 and gnomAD-Canada, allele frequency 0 versus the <0.1% threshold. PM4 (Moderate): in-frame 12-bp insertion lengthens MPL from 635 to 639 residues in the non-repeat transmembrane region. BP4 (Supporting): SpliceAI maximum delta score 0.032, below the <0.1 threshold for predicted benign splice impact. Synthesis: 1 moderate plus 1 supporting pathogenic against 1 supporting benign yields VUS under generic ACMG/AMP 2015 rules.

PM2 + PM4 + BP4 → 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 · 3 applied · 18 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 · 3
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met at supporting strength: absent from gnomAD v2.1, v4.1 and gnomAD-Canada with allele frequency 0, below the 0.1% threshold.
gnomAD v2.1 (exome, GRCh37 variant 1-43814952-C-CCGCTCTGGTGAT): search_status 'absent', evidence sentence 'Absent from gnomAD v2.1.'gnomAD v4.1 (GRCh38 variant chr1-43349281-C-CCGCTCTGGTGAT): search_status 'absent', evidence sentence 'Absent from gnomAD v4.1.'gnomAD-Canada v1.0 (HostSeq genomes): search_status 'absent', source_data ac=0, an=0, af=0.0, hom=0; evidence sentence 'Absent from gnomAD-Canada v1.0.'
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗
PM4 moderate Pathogenic
Met at moderate strength: an in-frame 12-bp insertion lengthens the MPL protein from 635 to 639 residues in a non-repeat region.
Variant class: NM_005373.2:c.1494_1495insGTGATCGCTCTG is a 12-nucleotide insertion in MPL exon 10 (VariantValidator vvdb_2025_3 / VV_SR_2025_02, RefSeq Select transcript NM_005373.2 -> NP_005364.1; variant_exonic_positions start_exon = end_exon = 10); the inserted length is an exact multiple of three, so the reading frame is preserved.Protein product: Mutalyzer normalization of this case variant returns NM_005373.2(NP_005364.1):p.(Leu498_His499insValIleAlaLeu) / p.(L498_H499insVIAL), with position_first = 498 and position_last_predicted = 502.Direct translation check of the reported protein strings: reference NP_005364.1 = 635 aa, predicted product = 639 aa; the reference and predicted sequences are identical apart from the inserted VIAL block (first divergence at residue 499) - a net gain of exactly 4 residues with no truncation, i.e. a pure in-frame length change rather than a stop-loss or null event.
spliceai ↗oncokb ↗
BP4 supporting Benign
Met at supporting strength: SpliceAI maximum delta score 0.032, below the <0.1 threshold for predicted benign splice impact.
SpliceAI Lookup (GRCh37, basic/mask=0, distance=500) for NM_005373.2:c.1494_1495insGTGATCGCTCTG (genomic 1-43814952-C-CCGCTCTGGTGAT): max delta score = 0.032 (DS_AG 0.032, DS_AL 0.000, DS_DG 0.029, DS_DL 0.018; DP_AG -18, DP_AL -332, DP_DG -279, DP_DL 376); source evidence sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).'BP4 threshold applied: SpliceAI max delta < 0.1 -> BP4 (supporting), per the ClinGen SVI Splicing Subgroup recommendation (Walker LC et al., Am J Hum Genet 2023;110(7):1046-1067, PMID:37352859).Independent concordance: Pangolin (from the same SpliceAI Lookup result) predicts SG 0.058 and SL -0.006, i.e. no gain or loss of a splice site, consistent with the negative SpliceAI result.
spliceai ↗
Assessed · not applied · 7 not met · 11 not assessed
Pathogenic
PS2 Not assessed: no proband record and no parental testing data were available to confirm or exclude a de novo occurrence.
PS3 Not assessed: no functional study of this variant was found, so a damaging effect on MPL function remains untested.
PS4 Not assessed: the variant is absent from ClinVar and unreported in patients, so increased prevalence in affected individuals could not be evaluated.
PM3 Not assessed: no proband genotype, phase information, or second pathogenic MPL allele was available to demonstrate the variant in trans.
PM6 Not assessed: no proband was reported to carry this variant de novo, with or without confirmed parental testing.
PP1 Not assessed: no pedigree or genotyped affected relatives were available, so co-segregation could not be counted.
PP3 Not met: SpliceAI maximum delta score 0.032, well below the >0.2 threshold required for supportive computational evidence.
PP4 Not assessed: no proband phenotype or clinical diagnosis was available to judge specificity for an MPL-related disorder.
PP5 Not met: the variant has no ClinVar record, so no reputable source asserts it is pathogenic.
Benign
BA1 Not met: allele frequency 0 across gnomAD v2.1, v4.1 and gnomAD-Canada, far below the >1% stand-alone threshold.
BS1 Not met: absent from all three gnomAD datasets (allele frequency 0), not greater than the low frequency expected for this rare disorder.
BS2 Not met: no germline occurrence in a healthy adult was found; the only recorded observations are somatic tumour events.
BS3 Not assessed: no functional assay was available, so a benign effect on protein function or splicing could not be demonstrated.
BS4 Not assessed: no family data or genotyped affected relatives were available to assess an explicit lack of segregation.
BP2 Not assessed: no individual was shown to carry this variant in cis or in trans with a pathogenic allele.
BP3 Not met: the insertion lies in the constrained transmembrane helix, not in a repetitive region of unknown function.
BP5 Not assessed: no proband diagnostic information was available to identify an alternative molecular cause for the phenotype.
BP6 Not met: the variant has no ClinVar record, so no reputable source asserts it is benign.
N/A · 7 PVS1 · PS1 · PM1 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency
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 ↗
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