Variant classification summary

NM_005373.2:c.1494_1495insGTGATCGCTCTG

MPL · NP_005364.1:p.(Leu498_His499insValIleAlaLeu) · NM_005373.2

GRCh37: chr1:43814952 C>CCGCTCTGGTGAT · GRCh38: chr1:43349281 C>CCGCTCTGGTGAT

Gene: MPL Transcript: NM_005373.2

Final call

VUS

PM2 supporting PM4 moderate BP4 supporting

Variant details

Gene

MPL

Transcript

NM_005373.2

Protein

NP_005364.1:p.(Leu498_His499insValIleAlaLeu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, v4.1 and gnomAD-Canada, allele frequency 0 versus the <0.1% threshold.

2

PM4 (Moderate): in-frame 12-bp insertion lengthens MPL from 635 to 639 residues in the non-repeat transmembrane region.

3

BP4 (Supporting): SpliceAI maximum delta score 0.032, below the <0.1 threshold for predicted benign splice impact.

4

Synthesis: 1 moderate plus 1 supporting pathogenic against 1 supporting benign yields VUS under generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 fallback: 1 Moderate (PM4) + 1 Supporting (PM2) pathogenic evidence with 1 Supporting benign criterion (BP4) meets no Pathogenic, Likely Pathogenic, Benign or Likely Benign combination, so the variant is classified as Variant of Uncertain Significance.

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: this is an in-frame insertion, not the nonsense, frameshift, or canonical splice class PVS1 requires.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: an in-frame insertion creates no single altered residue to match against a previously established pathogenic missense change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband record and no parental testing data were available to confirm or exclude a de novo occurrence.	final_classification_framework generic_acmg_combination_rules pvs1_gene_context clinvar
PS3	Not assessed	Not assessed: no functional study of this variant was found, so a damaging effect on MPL function remains untested.	oncokb clinvar
PS4	Not assessed	Not assessed: the variant is absent from ClinVar and unreported in patients, so increased prevalence in affected individuals could not be evaluated.	clinvar oncokb gnomad_v2 gnomad_v4 gnomad_canada
PM1	N/A	Not applicable: an in-frame insertion produces no single missense residue to test for mutational hot-spot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	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 gnomad_v4 gnomad_canada clinvar generic_acmg_combination_rules pvs1_gene_context
PM3	Not assessed	Not assessed: no proband genotype, phase information, or second pathogenic MPL allele was available to demonstrate the variant in trans.	clinvar pvs1_gene_context
PM4	Met	Met at moderate strength: an in-frame 12-bp insertion lengthens the MPL protein from 635 to 639 residues in a non-repeat region.	final_classification_framework generic_acmg_combination_rules pvs1_variant_assessment spliceai oncokb
PM5	N/A	Not applicable: an in-frame insertion is not a missense change, so there is no residue to compare with a pathogenic missense variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband was reported to carry this variant de novo, with or without confirmed parental testing.	final_classification_framework generic_acmg_combination_rules pvs1_gene_context clinvar
PP1	Not assessed	Not assessed: no pedigree or genotyped affected relatives were available, so co-segregation could not be counted.	final_classification_framework generic_acmg_combination_rules pvs1_gene_context
PP2	N/A	Not applicable: the criterion concerns missense variation, and this in-frame insertion creates no missense change to evaluate.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI maximum delta score 0.032, well below the >0.2 threshold required for supportive computational evidence.	spliceai final_classification_framework
PP4	Not assessed	Not assessed: no proband phenotype or clinical diagnosis was available to judge specificity for an MPL-related disorder.	clinvar oncokb
PP5	Not met	Not met: the variant has no ClinVar record, so no reputable source asserts it is pathogenic.	clinvar
BA1	Not met	Not met: allele frequency 0 across gnomAD v2.1, v4.1 and gnomAD-Canada, far below the >1% stand-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: absent from all three gnomAD datasets (allele frequency 0), not greater than the low frequency expected for this rare disorder.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: no germline occurrence in a healthy adult was found; the only recorded observations are somatic tumour events.	gnomad_v2 gnomad_v4 gnomad_canada clinvar oncokb
BS3	Not assessed	Not assessed: no functional assay was available, so a benign effect on protein function or splicing could not be demonstrated.	oncokb clinvar
BS4	Not assessed	Not assessed: no family data or genotyped affected relatives were available to assess an explicit lack of segregation.	final_classification_framework generic_acmg_combination_rules pvs1_gene_context
BP1	N/A	Not applicable: the criterion applies to missense variants, and this in-frame insertion creates no missense change.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no individual was shown to carry this variant in cis or in trans with a pathogenic allele.	clinvar pvs1_gene_context
BP3	Not met	Not met: the insertion lies in the constrained transmembrane helix, not in a repetitive region of unknown function.	final_classification_framework generic_acmg_combination_rules pvs1_variant_assessment
BP4	Met	Met at supporting strength: SpliceAI maximum delta score 0.032, below the <0.1 threshold for predicted benign splice impact.	spliceai final_classification_framework
BP5	Not assessed	Not assessed: no proband diagnostic information was available to identify an alternative molecular cause for the phenotype.	clinvar
BP6	Not met	Not met: the variant has no ClinVar record, so no reputable source asserts it is benign.	clinvar
BP7	N/A	Not applicable: BP7 covers synonymous variants, and this insertion alters the encoded protein sequence.	generic_acmg_combination_rules

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