MET c.3082G>C, p.(Asp1028His)

Reasoning

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This supports PM2 because the allele is not observed in the available population datasets. The underlying records in the bundle provide absence statements but no allele-number, coverage, or ancestry-specific denominator details, so confirmation of database quality and applicability should receive human review.

Rule

generic_acmg_amp: PM2 supporting when the variant is absent or extremely rare in population databases, with disease prevalence and penetrance considered where available

Evidence considered

• gnomAD v2.1 reports NM_001127500.2:c.3082G>C as absent.
• gnomAD v4.1 reports NM_001127500.2:c.3082G>C as absent.
• gnomAD-Canada v1.0 reports NM_001127500.2:c.3082G>C as absent.
• The case bundle identifies no applicable MET-specific CSPEC/VCEP framework, so generic ACMG/AMP criteria are used.

Still missing

• The bundled gnomAD records do not include allele-number, coverage, or ancestry-specific denominator details.
• No MET-specific disease prevalence, penetrance, or maximum credible population-frequency threshold was provided.

Sources

Reasoning

No MET-specific VCEP/CSPEC PP3/BP4 lookup material is available for this case (framework_mode=generic_acmg, cspec.found=false, vcep_materials empty), so generic ACMG in-silico evidence applies. NM_001127500.2:c.3082G>C (p.Asp1028His) is a missense substitution, but SpliceAI predicts a high-confidence splice-donor-loss event: DS_DL=0.925 at DP_DL=0 (i.e. the predicted loss is at the annotated donor position itself), with a secondary DS_DG=0.477 donor-gain signal; max delta score = 0.925. Using the SpliceAI developer publication's own precision-recall bands (delta >=0.8 corresponds to the high-precision tier), a score of 0.925 is well above the high-precision cutoff and supports a deleterious splicing effect, satisfying PP3 at supporting strength under the generic ACMG framework (no calibrated evidence exists in this pipeline to justify an upgrade to moderate/strong for SpliceAI in the absence of a gene-specific VCEP splicing calibration). On the missense in-silico sub-path, REVEL=0.374 falls in the indeterminate zone (neither reaching a supporting-pathogenic nor supporting-benign REVEL threshold) and BayesDel (-0.0818303) has no verified published threshold available to this pipeline, so neither contributes to PP3 independently; the splice-path evidence alone is sufficient and is not double counted against the missense path.

Rule

generic_acmg_PP3_splicing_high_confidence_spliceai

Evidence considered

• SpliceAI donor-loss delta score DS_DL=0.925 (DP_DL=0), donor-gain DS_DG=0.477, max delta score=0.925, from the SpliceAI Lookup tool run for NM_001127500.2:c.3082G>C.
• SpliceAI's own precision-recall calibration (Jaganathan et al. 2019, PMID 30661751) reports that delta scores >=0.8 fall in a high-precision band strongly consistent with a splice-altering effect; this variant's max delta of 0.925 exceeds that band.
• REVEL score 0.374 (local REVEL v1.3 lookup) is in an indeterminate range that does not meet a supporting-strength pathogenic or benign REVEL threshold, so it is not used to support PP3.
• BayesDel score -0.0818303 (local BayesDel_170824_noAF lookup) has no verified published calibration threshold available to this pipeline (per project-level review, BayesDel thresholds are not currently confirmed against a named publication), so it is treated as not_available and not used to support or refute PP3.

Still missing

• No RNA/minigene or transcript-level splicing assay evidence available to confirm the SpliceAI prediction experimentally.
• No MET-specific VCEP splicing threshold table available to determine whether a stronger-than-supporting strength is warranted for this SpliceAI score.

Sources

Reasoning

PP5 is not met: the exact-variant ClinVar search returned no record for NM_001127500.2:c.3082G>C, and no expert-panel Pathogenic or Likely pathogenic classification is present.

Rule

Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.

Evidence considered

• ClinVar exact-variant search returned no result; variation ID, classification, review status, and citations are empty.
• No qualifying exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion is available; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.

Sources

Reasoning

BA1 requires an allele frequency high enough to establish a stand-alone benign observation. NM_001127500.2:c.3082G>C (MET p.Asp1028His) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; no population allele frequency or count approaches a BA1 threshold.

Rule

generic_acmg_amp: BA1 requires population frequency above the stand-alone benign threshold; absence cannot satisfy BA1

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.

Sources

Reasoning

BS1 requires an allele frequency greater than expected for the disorder. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so no elevated population frequency is present to support BS1.

Rule

generic_acmg_amp: BS1 requires an allele frequency greater than expected for the disorder; absence cannot satisfy BS1

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.

Sources

Reasoning

No MET-specific VCEP/CSPEC PP3/BP4 lookup material is available for this case, so generic ACMG in-silico evidence applies. The dominant computational signal for this variant is the SpliceAI splice-donor-loss prediction (DS_DL=0.925, max delta 0.925), which is deleterious-direction evidence, not benign-direction, so BP4 cannot be met on the splice path. On the missense in-silico path, REVEL=0.374 sits in an indeterminate zone that does not reach a supporting-strength benign threshold, and BayesDel (-0.0818303) is not usable for PP3/BP4 in this pipeline because no verified published calibration threshold can be named for it. With no in-silico predictor reaching a benign-supporting threshold and the splice predictor actively pointing toward a damaging effect, BP4 is not met.

Rule

generic_acmg_BP4_not_met_deleterious_splice_signal

Evidence considered

• SpliceAI donor-loss delta score DS_DL=0.925 (max delta 0.925) indicates a predicted deleterious splicing effect, which is inconsistent with applying BP4.
• REVEL score 0.374 does not reach a supporting-strength benign REVEL threshold, so it does not support BP4.
• BayesDel score -0.0818303 has no verified published calibration threshold available to this pipeline and is therefore treated as not_available for BP4, consistent with treatment of BayesDel for PP3.

Still missing

• No calibrated benign-direction threshold reached by REVEL or SpliceAI for this variant.
• BayesDel cannot be used for BP4 without a named, citable publication establishing its threshold.

Sources

Reasoning

BP6 is not met: the exact-variant ClinVar search returned no record for NM_001127500.2:c.3082G>C, and no expert-panel Benign or Likely benign classification is present.

Rule

Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.

Evidence considered

• ClinVar exact-variant search returned no result; variation ID, classification, review status, and citations are empty.
• No qualifying exact-variant ClinVar expert-panel Benign or Likely benign assertion is available; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.

Sources

Reasoning

PS1 requires an established pathogenic variant that produces the identical amino acid change (p.Asp1028His) via a different nucleotide substitution. The ClinVar lookup performed in this case searched only for the exact variant NM_001127500.2:c.3082G>C and returned no result (variant absent from ClinVar); no search was performed for alternate codon changes at residue 1028 that would also yield p.Asp1028His and be classified pathogenic/likely pathogenic. No such comparator was surfaced anywhere else in the case bundle.

Evidence considered

• case_summary.json ClinVar lookup for this exact variant returned exact_match=false and evidence_sentence 'This variant is absent from ClinVar', but this search targeted only the exact c.3082G>C variant, not other codon-1028 substitutions producing the same amino acid change.

Still missing

• No targeted ClinVar/literature search was performed for alternate nucleotide substitutions at MET codon 1028 producing the same p.Asp1028His change classified as pathogenic/likely pathogenic.
• No MET-specific VCEP/CSPEC PS1 rule was available (cspec.found=false, gene_vcep_dir=null) to define codon-level PS1 application criteria.

Sources

Reasoning

No proband-level de novo assessment is possible from the case-evidence bundle. The bundle contains no documented parental testing, confirmed maternity/paternity, parental genotypes, or de novo observation for NM_001127500.2:c.3082G>C (MET p.Asp1028His).

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo occurrence in the proband, with maternity/paternity confirmed and phenotype consistent with the relevant disorder; strength cannot be assigned without those data.

Evidence considered

• The governing framework retrieved for this case is the generic ACMG/AMP fallback because no MET-specific VCEP/CSPEC framework was available.
• The consolidated case-evidence bundle provides no parental-testing or confirmed de novo evidence for this variant.

Still missing

• Proband phenotype and clinical indication
• Testing results for both biological parents
• Confirmation of maternity and paternity
• Assessment of parental mosaicism and test sensitivity
• Independent confirmation that the variant is absent in both parents

Sources

Reasoning

No gene-specific VCEP/CSPEC framework is available for MET (cspec.found=false, framework_mode=generic_acmg), so generic ACMG PS3 applies. No functional assay data (kinase activity assays, splicing minigene assays, cell-based proliferation/transformation assays, or any other validated functional study) for NM_001127500.2:c.3082G>C (p.Asp1028His) was found anywhere in the case bundle: prefetch.json contains no functional assay source, literature_pass.json reports zero PMIDs found, and the PVS1-targeted germline literature search returned only gene-context papers unrelated to this specific variant's functional characterization. No source in this bundle provides validated in vitro/in vivo assay results, assay controls, or biological relevance data for this exact variant.

Still missing

• No functional assay evidence (biochemical, cell-based, or splicing) identified for this variant in any source reviewed.
• No CSPEC/VCEP functional assay specification available for MET to define approved assay types or strength calibration.

Reasoning

PS4 cannot be assessed because the case bundle contains no phenotype-defined germline case-control cohort, affected-case and control counts, or enrichment statistic for NM_001127500.2:c.3082G>C (MET p.Asp1028His). The COSMIC observation is somatic cancer occurrence and is not evidence of germline case-control enrichment.

Rule

PS4 requires statistically significant enrichment of the variant in affected individuals compared with appropriate controls; somatic database presence alone is insufficient.

Evidence considered

• COSMIC reports COSV59259530 13 times in somatic cancers, but provides no germline case-control analysis.
• The literature pass contains zero PMIDs and no relevant phenotype-prevalence publication.

Still missing

• A phenotype-defined affected cohort and appropriate controls are needed.
• Variant counts, cohort methodology, and an odds ratio or equivalent enrichment statistic are unavailable.

Reasoning

No MET-specific VCEP/CSPEC framework defining a mutational hotspot or critical functional domain boundary around residue 1028 was available in this case (cspec.found=false, gene_vcep_dir=null). The case bundle's cancerhotspots.org lookup (a somatic-cancer significance-testing resource, not a registered source_registry key in this case) reported that D1028 does not lie in a statistically significant hotspot, but this tool is not designed to assess ACMG PM1 germline functional-domain enrichment and is not present as a citable source_registry entry, so it cannot be used as a grounded evidence_ref here. No independent domain/structural annotation (e.g., UniProt kinase-domain boundaries, ClinGen-curated critical region) was retrieved in this case to establish or refute PM1.

Still missing

• No MET-specific critical/functional domain definition (e.g., kinase domain boundaries, juxtamembrane region) with mutational density data was retrieved to evaluate PM1 at residue 1028.
• The cancerhotspots.org check exists only in evidence.json/case_summary.json and lacks a corresponding source_registry key, so it cannot be cited as evidence_refs for this determination without violating the exact-key requirement.

Reasoning

No applicable MET-specific VCEP or gene-specific framework was available, so the generic ACMG/AMP PM3 concept was considered. The case bundle contains no affected-proband observations, family segregation data, phase information, or confirmed pathogenic/likely pathogenic allele reported in trans with NM_001127500.2:c.3082G>C. PM3 cannot therefore be assigned.

Rule

Generic ACMG/AMP PM3: pathogenic or likely pathogenic variants observed in trans in affected individuals with a recessive disorder; strength depends on the number and quality of informative observations.

Evidence considered

• The case bundle reports no literature PMIDs, no ClinVar record, and no VCEP materials for this variant.
• The case bundle provides no affected-proband, pedigree, inheritance, compound-heterozygous, or phase observations relevant to PM3.

Still missing

• Affected-proband or family-level observations for this variant are unavailable.
• No confirmed pathogenic/likely pathogenic allele and no experimentally established phase in trans are documented.

Reasoning

No unconfirmed de novo occurrence is documented in the case-evidence bundle. There is no proband/parent genotype information, phenotype description, or publication-based case report supporting NM_001127500.2:c.3082G>C as apparently de novo.

Rule

Generic ACMG/AMP PM6 may be considered for an apparently de novo occurrence when parental testing is unavailable, but requires documented proband and phenotype context; no strength is assigned here.

Evidence considered

• The governing framework retrieved for this case is the generic ACMG/AMP fallback because no MET-specific VCEP/CSPEC framework was available.
• The consolidated case-evidence bundle contains no case report, proband record, parental results, or apparently de novo observation for this variant.

Still missing

• A documented proband carrying the variant
• Parental testing or a documented reason that parental testing was unavailable
• Phenotype consistency with a relevant MET-associated disorder
• Evidence supporting maternity and paternity or the limitations of their confirmation

Sources

Reasoning

No familial segregation data are available for NM_001127500.2:c.3082G>C. The case-evidence bundle does not identify affected relatives, unaffected relatives, informative meioses, or genotype/phenotype results from any family members.

Rule

Generic ACMG/AMP PP1 requires cosegregation of the variant with disease in affected family members; supporting strength depends on the number and informativeness of meioses and cannot be assigned without family data.

Evidence considered

• The governing framework retrieved for this case is the generic ACMG/AMP fallback because no MET-specific VCEP/CSPEC framework was available.
• The consolidated case-evidence bundle contains no segregation study, pedigree, family genotypes, or informative meioses for this variant.

Still missing

• Family pedigree and phenotype information
• Genotypes of affected relatives
• Genotypes of unaffected relatives
• Number of informative meioses
• Assessment of phenotype specificity and phenocopies

Sources

Reasoning

PP2 requires establishing that missense variation is a common mechanism of disease in MET with a low rate of benign missense variation. No MET-specific VCEP/CSPEC PP2 specification, missense constraint metric (e.g., gnomAD missense Z-score/O:E), or curated benign-missense-rate statement was present anywhere in the case bundle (cspec.found=false; no constraint data retrieved in prefetch/evidence/case_summary).

Still missing

• No missense constraint metric (gnomAD Z-score, missense O:E) for MET was retrieved in this case.
• No MET-specific VCEP/CSPEC statement on missense as a disease mechanism was available to ground a PP2 determination.

Reasoning

PP4 cannot be assessed because no patient phenotype, clinical diagnosis, family history, or disease-specific phenotype spectrum is provided. No MET-specific specification was retrieved, so the generic ACMG/AMP rule applies.

Rule

PP4 may be used when the patient's phenotype or family history is highly specific for a disease with a single-gene etiology; absent phenotype information is insufficient.

Evidence considered

• The case bundle contains no phenotype description or phenotype-defined case evidence.
• The bundle reports no applicable MET ClinGen CSPEC/VCEP framework; generic ACMG/AMP fallback was used.

Still missing

• The patient's clinical phenotype and diagnostic indication are unavailable.
• A highly specific phenotype-genotype correlation for the relevant disease context is not documented.

Reasoning

No evidence in the case bundle documents the variant in healthy adults, unaffected individuals, or healthy homozygotes. Absence from population databases is relevant to PM2 but does not establish the BS2 observation required for this criterion.

Rule

generic_acmg_amp: BS2 requires observation in healthy adults or healthy homozygotes despite a disorder expected to manifest early and fully penetrantly

Still missing

• No documented healthy-adult carriers or healthy homozygotes were identified.
• No phenotype-confirmed control cohort or family segregation dataset was provided for BS2 assessment.

Reasoning

No gene-specific VCEP/CSPEC framework is available for MET (cspec.found=false, framework_mode=generic_acmg), so generic ACMG BS3 applies. No functional assay data showing normal/benign functional impact for NM_001127500.2:c.3082G>C (p.Asp1028His) was found anywhere in the case bundle. literature_pass.json reports zero PMIDs found, and no source_registry entry corresponds to a functional/assay study of this variant.

Still missing

• No functional assay evidence (biochemical, cell-based, or splicing) identified for this variant in any source reviewed.
• No CSPEC/VCEP functional assay specification available for MET to define approved assay types or strength calibration.

Reasoning

No non-segregation evidence is available. The case-evidence bundle does not document any clearly affected individual who lacks the variant, nor does it provide a pedigree or informative relatives suitable for evaluating BS4.

Rule

Generic ACMG/AMP BS4 requires a well-established affected individual or family member who lacks the variant, with appropriate consideration of phenotype specificity, penetrance, and phenocopies; no assessment is possible here.

Evidence considered

• The governing framework retrieved for this case is the generic ACMG/AMP fallback because no MET-specific VCEP/CSPEC framework was available.
• The consolidated case-evidence bundle contains no affected relative reported as negative for the variant and no other non-segregation evidence.

Still missing

• Affected relatives with reliable clinical phenotyping
• Variant testing results for affected relatives
• Pedigree structure and age-dependent penetrance context
• Evaluation for phenocopies and reduced penetrance

Sources

Reasoning

BP1 requires establishing that MET is a gene where disease is primarily caused by truncating/loss-of-function variants such that missense variants are generally benign. No MET-specific VCEP/CSPEC BP1 specification or gene-level missense-vs-truncating mechanism statement grounded to a citable source was available in this case bundle to support or refute that characterization.

Still missing

• No MET-specific VCEP/CSPEC statement characterizing the gene's primary disease mechanism (missense-driven vs. truncating-driven) was available to ground a BP1 determination.
• The pvs1_gene_context literature search in this case surfaced mostly non-MET-gene papers (BRCA2, ANK1, CTNNA1) and only one MET-specific paper (PMID:26637977, an exon-skipping splicing mechanism, not a classic truncating-LOF missense-benign argument), so it does not establish a reliable gene-level mechanism basis for BP1.

Reasoning

No applicable MET-specific VCEP or gene-specific framework was available, so the generic ACMG/AMP BP2 concept was considered. The case bundle contains no observations establishing this variant in trans with a pathogenic/likely pathogenic variant for a dominant disorder or in cis with a pathogenic/likely pathogenic variant for a recessive disorder. BP2 cannot therefore be assigned.

Rule

Generic ACMG/AMP BP2: variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder.

Evidence considered

• The case bundle provides no family segregation, parental testing, affected-proband, or phase observations relevant to BP2.
• The case bundle reports no literature PMIDs, no ClinVar record, and no VCEP materials that establish a qualifying cis or trans observation.

Still missing

• Inheritance mode and disease-relevant parental or family phase data are unavailable.
• No confirmed pathogenic/likely pathogenic variant and no cis/trans relationship are documented for this case.

Reasoning

BP5 cannot be assessed because no affected individual, clinical phenotype, or independent alternate molecular basis for the disease is provided. The somatic COSMIC record does not establish an alternate molecular etiology for a clinical case.

Rule

BP5 requires the variant to be found in an affected individual with an alternate molecular basis for the disease; somatic database occurrence alone is insufficient.

Evidence considered

• COSMIC reports somatic cancer observations for the variant but does not provide a clinical case with an alternate molecular basis.
• No case-level molecular diagnosis or alternate pathogenic variant was included in the case bundle.

Still missing

• A documented affected individual and phenotype are needed.
• An independent molecular explanation for the phenotype, distinct from this variant, is needed.