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

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: the variant is absent from gnomAD v2.1 and v4.1.

2

PM4 moderate: the in-frame insertion adds four amino acids at p.Leu498_His499 in the MPL transmembrane region.

Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate criterion plus one supporting criterion does not reach a defined pathogenic, likely pathogenic, benign, or likely benign combination, resulting 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.1494_1495insGTGATCGCTCTG in MPL is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_005364.1:p.(Leu498_His499insValIleAlaLeu). 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	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_005373.2:c.1494_1495insGTGATCGCTCTG in MPL is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_005364.1:p.(Leu498_His499insValIleAlaLeu). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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
PS2	Not assessed	Not assessed: no proband-parent testing or documented de novo observation is available.
PS3	Not assessed	Not assessed: no validated MPL functional assay, controls, or quantitative result was available for this in-frame insertion.	oncokb
PS4	Not assessed	Not assessed: no affected-case series, control comparison, odds ratio, or other case-control enrichment measure was reported for this exact variant.	generic_acmg_combination_rules
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_005373.2:c.1494_1495insGTGATCGCTCTG in MPL is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_005364.1:p.(Leu498_His499insValIleAlaLeu). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observation or phase-resolved pathogenic variant in trans is documented for this variant.
PM4	Met	Met, moderate: the in-frame insertion adds four amino acids at p.Leu498_His499 within a non-repetitive transmembrane-region sequence.	generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_005373.2:c.1494_1495insGTGATCGCTCTG in MPL is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_005364.1:p.(Leu498_His499insValIleAlaLeu). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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
PM6	Not assessed	Not assessed: no apparently de novo observation with unconfirmed parental status is documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or segregation counts are documented.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_005373.2:c.1494_1495insGTGATCGCTCTG in MPL is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_005364.1:p.(Leu498_His499insValIleAlaLeu). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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
PP3	N/A	Not applicable: the exonic in-frame insertion changes protein length and is outside PP3's missense or intronic/splice-region scope.
PP4	Not assessed	Not assessed: no individual clinical phenotype or disease-specific feature set was provided to evaluate phenotype specificity for PP4.	generic_acmg_combination_rules oncokb
PP5	Not met	Not met: the exact variant is absent from ClinVar, with no expert-panel Pathogenic or Likely pathogenic classification available.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having an allele frequency >=0.05 required for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report no carriers, providing no evidence of healthy adult homozygotes for BS2.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no validated MPL assay demonstrated preserved function for this in-frame insertion.	oncokb
BS4	Not assessed	Not assessed: no reliable non-segregation observations in informative unaffected relatives are documented.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_005373.2:c.1494_1495insGTGATCGCTCTG in MPL is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_005364.1:p.(Leu498_His499insValIleAlaLeu). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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
BP2	Not assessed	Not assessed: no documented pathogenic partner variant or cis/trans phase information is available for this variant.
BP3	Not met	Not met: p.Leu498_His499 is a four-amino-acid insertion in the specific MPL transmembrane region, not a functionless repetitive protein segment.	generic_acmg_combination_rules
BP4	N/A	Not applicable: the exonic in-frame insertion changes protein length and is outside BP4's missense or intronic/splice-region scope.
BP5	Not assessed	Not assessed: no patient-level alternate molecular diagnosis or evidence that another pathogenic variant explains the phenotype was provided.	generic_acmg_combination_rules
BP6	Not met	Not met: the exact variant is absent from ClinVar, with no expert-panel Benign or Likely benign classification available.	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.1494_1495insGTGATCGCTCTG in MPL is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_005364.1:p.(Leu498_His499insValIleAlaLeu). 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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