MET c.3073_3082+25del, p.?

Reasoning

No applicable MET-specific VCEP/CSPEC was identified, so the supplied generic PM2 threshold of allele frequency <=0.0001 was used at supporting strength. The exact variant NM_001127500.2:c.3073_3082+25del is reported as absent from gnomAD v2.1 and gnomAD v4.1, yielding an observed allele frequency of 0, which is below the threshold. It is also reported absent from the available gnomAD v2.1 non-cancer and v3.1 non-cancer searches; because no governing specification requires those subsets, the default all-comers datasets are the primary basis.

Rule

Generic PM2: allele frequency <=0.0001, applied at supporting strength; absent in the default all-comers gnomAD datasets gives observed frequency 0.

Evidence considered

• No applicable MET-specific VCEP/CSPEC was available; the supplied generic PM2 threshold is allele frequency <=0.0001 at supporting strength.
• gnomAD v2.1 reports the exact variant as absent, corresponding to observed frequency 0.
• gnomAD v4.1 reports the exact variant as absent, corresponding to observed frequency 0.
• The available gnomAD v2.1 non-cancer and v3.1 non-cancer searches also report absence; they were not required as the governing specification is unavailable.

Sources

Reasoning

PP3 applies because this is an intronic/splice-region deletion with an unresolved protein consequence, so the SpliceAI pathway is in scope. SpliceAI reports a maximum delta score of 0.943 (DS_DL), which meets the supplied generic PP3 moderate threshold of >=0.5 from the SpliceAI high-precision calibration (Jaganathan et al. 2019, PMID:30661751). No governing MET-specific VCEP specification was available, so the generic threshold applies. This prediction is used once for PP3 and is not double-counted for BP4.

Rule

Generic SpliceAI PP3 moderate: maximum delta score >=0.5.

Evidence considered

• The variant is NM_001127500.2:c.3073_3082+25del, an intronic/splice-region deletion with protein consequence p.?, so PP3 is evaluated through SpliceAI rather than missense predictors.
• SpliceAI maximum delta score is 0.943 (DS_DL), exceeding the supplied PP3 moderate cutoff of >=0.5.
• The supplied cutoff is the SpliceAI high-precision cutoff from Jaganathan et al. 2019 (PMID:30661751).

Sources

Reasoning

The exact normalized variant NM_001127500.2:c.3073_3082+25del was not found in ClinVar, with no variation ID, classification, review status, or expert-panel assertion. PP5 is therefore not met because there is no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary or aggregate assertions would not qualify.

Rule

Apply PP5 at supporting strength only for an exact-variant ClinVar Expert Panel classification of Pathogenic or Likely pathogenic; laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar exact-variant searches returned no result for NM_001127500.2:c.3073_3082+25del, and the submission audit is empty; consequently no expert-panel Pathogenic or Likely pathogenic assertion exists in the available record.

Sources

Reasoning

No applicable MET-specific VCEP/CSPEC was identified, so the supplied generic ACMG/AMP BA1 threshold of allele frequency >=0.05 was used. The variant NM_001127500.2:c.3073_3082+25del is absent from gnomAD v2.1 and gnomAD v4.1, with the case records reporting no observed alleles; therefore its observed frequency is 0 and does not meet the stand-alone benign threshold. The non-cancer subset records are also absent, but do not change the conclusion.

Rule

Generic BA1: allele frequency >=0.05; absent variant has observed frequency 0 and does not meet BA1.

Evidence considered

• No applicable MET-specific VCEP/CSPEC was available; the supplied generic ACMG/AMP BA1 stand-alone threshold is allele frequency >=0.05.
• gnomAD v2.1 reports the exact variant as absent, with no observed allele count or frequency.
• gnomAD v4.1 reports the exact variant as absent, with no observed allele count or frequency.
• The available non-cancer subset searches also report absence, but no disease-specific population threshold supersedes the generic rule.

Sources

Reasoning

No applicable MET-specific VCEP/CSPEC was identified, so the supplied generic BS1 threshold of allele frequency >=0.01 was used. The exact variant is absent from gnomAD v2.1 and gnomAD v4.1, with no observed alleles reported; its observed frequency is therefore 0 and does not meet BS1. The non-cancer subset records are likewise absent and provide no contrary frequency signal.

Rule

Generic BS1: allele frequency >=0.01; absent variant has observed frequency 0 and does not meet BS1.

Evidence considered

• No applicable MET-specific VCEP/CSPEC was available; the supplied generic BS1 threshold is allele frequency >=0.01.
• gnomAD v2.1 reports the exact variant as absent, with no observed allele count or frequency.
• gnomAD v4.1 reports the exact variant as absent, with no observed allele count or frequency.
• The available non-cancer subset searches also report absence.

Sources

Reasoning

BP4 applies because this is an intronic/splice-region deletion and the SpliceAI pathway is in scope. SpliceAI reports a maximum delta score of 0.943, which does not meet the supplied generic BP4 supporting threshold of <=0.1 from Jaganathan et al. 2019 (PMID:30661751). The same SpliceAI prediction is not reused to support PP3 and BP4 simultaneously.

Rule

Generic SpliceAI BP4 supporting: maximum delta score <=0.1.

Evidence considered

• The variant is an intronic/splice-region deletion, making the SpliceAI-based BP4 pathway applicable.
• SpliceAI maximum delta score is 0.943, which is above the supplied BP4 supporting cutoff of <=0.1.
• The supplied cutoff is the SpliceAI recommended cutoff from Jaganathan et al. 2019 (PMID:30661751); the prediction is not double-counted with PP3.

Sources

Reasoning

The exact normalized variant NM_001127500.2:c.3073_3082+25del was not found in ClinVar, with no variation ID, classification, review status, or expert-panel assertion. BP6 is therefore not met because there is no exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary or aggregate assertions would not qualify.

Rule

Apply BP6 at supporting strength only for an exact-variant ClinVar Expert Panel classification of Benign or Likely benign; laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar exact-variant searches returned no result for NM_001127500.2:c.3073_3082+25del, and the submission audit is empty; consequently no expert-panel Benign or Likely benign assertion exists in the available record.

Sources

Reasoning

No MET CSPEC/VCEP specification is available, so the generic ClinGen SVI PVS1 framework applies. The normalized variant is NM_001127500.2:c.3073_3082+25del, a deletion beginning in exon 14 and extending 25 bases into intron 14i; VariantValidator reports NP_001120972.1:p.? and classifies the consequence as unresolved rather than nonsense, frameshift, or canonical +/-1,2 splice loss. SpliceAI predicts substantial splice impact (max delta 0.943), but this prediction does not by itself establish exon loss, NMD, or a null protein product. Therefore PVS1 cannot be assigned or strength-tiered without transcript-level consequence evidence, such as RNA analysis or validated splice characterization.

Rule

ClinGen SVI PVS1 recommendations (PMC6185798): PVS1 requires an established loss-of-function consequence; non-canonical splice prediction alone is insufficient to assign PVS1.

Evidence considered

• The generic ClinGen SVI PVS1 framework is the governing framework because no MET-specific CSPEC/VCEP rule was retrieved.
• VariantValidator normalizes the variant to NM_001127500.2:c.3073_3082+25del, places its endpoints in exon 14 and intron 14i, and reports NP_001120972.1:p.? with no resolved consequence class.
• SpliceAI reports DS_DL 0.943 as the maximum delta score, indicating predicted splice impact but not proving a null transcript or protein product.

Still missing

• RNA or other validated transcript evidence is needed to determine whether exon 14 or adjacent sequence is aberrantly spliced.
• The resulting open reading frame, protein consequence, and NMD susceptibility are not established.
• Exon criticality and transcript-specific relevance for a loss-of-function mechanism are not established.

Sources

Reasoning

No proband-level phenotype, parental testing, maternity/paternity confirmation, or other case-level evidence establishing a de novo occurrence was provided. Therefore, PS2 cannot be assessed under the generic ACMG/AMP framework.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo variant in the affected proband, with maternity and paternity confirmed; strength depends on the quality and extent of de novo evidence.

Evidence considered

• The available case evidence contains no proband-level phenotype, parental testing results, or confirmed de novo status.
• The MET case has no applicable VCEP/CSPEC specification; generic ACMG/AMP criteria are therefore the fallback, but the required de novo observations are absent.

Still missing

• Documented proband genotype and phenotype.
• Parental genotype results for the variant.
• Confirmation of maternity and paternity, if available.
• Assessment of parental mosaicism and technical confirmation method.

Reasoning

No validated experimental assay evaluating the effect of NM_001127500.2:c.3073_3082+25del on MET splicing, transcript expression, protein function, or a biologically relevant cellular phenotype was identified. SpliceAI predicts a splice impact with a max delta score of 0.943, but this computational prediction is not functional assay evidence and cannot establish PS3 or its strength.

Evidence considered

• No publication or source in the case evidence reports a validated functional assay for NM_001127500.2:c.3073_3082+25del.
• SpliceAI reports a maximum delta score of 0.943 and predicts possible splice impact, but computational prediction alone does not satisfy PS3.

Still missing

• A validated assay directly evaluating the variant's effect on MET splicing, transcript expression, protein activity, or a relevant cellular phenotype is needed.
• Assay controls and quantitative comparison with wild-type and appropriate loss-of-function or pathogenic controls are unavailable.

Sources

Reasoning

No case-control cohort, affected-case enrichment, odds ratio, or other prevalence statistic for this exact MET variant was identified. The available case materials contain no affected-versus-control comparison establishing enrichment, so PS4 cannot be assessed.

Rule

PS4 requires statistically significant enrichment of the variant in affected individuals compared with appropriate controls, or a validated phenotype-specific equivalent; no numeric threshold was available or applicable here.

Evidence considered

• The case evidence reports no literature PMIDs and provides no case-control cohort, affected-case count, control count, odds ratio, or other exact-variant prevalence statistic.

Still missing

• Exact-variant case-control data or a validated affected-case enrichment statistic is unavailable.

Reasoning

No MET-specific VCEP or gene-specific framework was retrieved, so the generic ACMG/AMP framework applies. The available case evidence documents only the variant description and database/prediction results; it contains no affected-proband observations, a pathogenic or likely pathogenic variant in trans, phase information, family testing, or inheritance data. Therefore, PM3 cannot be assessed.

Rule

PM3 requires observation of the variant in trans with a pathogenic or likely pathogenic variant in an affected individual; without phase and affected-proband evidence, it is not assessable.

Evidence considered

• The case evidence identifies NM_001127500.2:c.3073_3082+25del but provides no affected-proband, phase, trans-variant, family-segregation, or inheritance observations relevant to PM3.
• No applicable MET-specific VCEP framework was retrieved; generic ACMG/AMP assessment is therefore required.

Still missing

• Affected-proband observations are not documented.
• A pathogenic or likely pathogenic variant in trans is not documented.
• Cis/trans phase and inheritance information are not documented.

Reasoning

No case-level observation of the variant as apparently de novo without confirmed maternity and paternity was provided. Therefore, PM6 cannot be assessed under the generic ACMG/AMP framework.

Rule

Generic ACMG/AMP PM6 may be used for an apparently de novo variant when maternity and paternity are not confirmed; the observation must still be documented in an affected proband.

Evidence considered

• The available case evidence contains no report of an apparently de novo variant in the proband and no parental-testing information.
• The MET case has no applicable VCEP/CSPEC specification; generic ACMG/AMP criteria are therefore the fallback, but the required de novo observations are absent.

Still missing

• Documented proband genotype and phenotype.
• Parental testing or explicit evidence that maternity and paternity were not confirmed.
• Technical confirmation and evaluation for parental mosaicism.

Reasoning

No affected relatives, informative meioses, cosegregation data, or phenotype-consistent family observations were provided. Therefore, PP1 cannot be assessed under the generic ACMG/AMP framework.

Rule

Generic ACMG/AMP PP1 supports pathogenicity when a variant cosegregates with disease in affected family members; strength should reflect the number and informativeness of segregations.

Evidence considered

• The available case evidence contains no pedigree, affected-relative genotypes, informative meioses, or segregation observations.
• The MET case has no applicable VCEP/CSPEC specification; generic ACMG/AMP criteria are therefore the fallback, but no segregation dataset is available.

Still missing

• Pedigree identifying affected and unaffected relatives.
• Genotypes for informative relatives.
• Number of informative meioses and phenotype consistency.
• Independent segregation analysis excluding related or duplicate observations.

Reasoning

No clinical phenotype, phenotype checklist, diagnostic criteria, or disease-specific presentation for an individual carrying this exact MET variant was provided. Although MET-associated osteofibrous dysplasia is referenced in the broader gene-level search context, no variant-carrier phenotype is documented here; therefore phenotype specificity cannot be assessed.

Rule

PP4 may be applied when the patient's phenotype or family history is highly specific for a disease with a single-gene etiology; no patient-specific phenotype evidence is available.

Evidence considered

• The case materials do not document a patient phenotype, diagnostic features, or a specific disease presentation for this exact MET variant.

Still missing

• A documented carrier phenotype and disease-specific clinical correlation are unavailable.

Reasoning

BS2 requires the variant to be observed in healthy adults, typically including homozygotes for a dominant disease or hemizygotes for an X-linked disease, with phenotype and penetrance considered. The available case evidence only reports that the variant is absent from gnomAD datasets; it provides no healthy-carrier phenotype, homozygote observation, inheritance, disease-prevalence, or penetrance analysis. Absence from population databases cannot itself establish BS2.

Rule

BS2 requires healthy-adult observation appropriate to the inheritance model; no qualifying observation is available.

Evidence considered

• BS2 requires observation in healthy adults, with zygosity and disease-model context; no such observation is reported for this exact variant.
• The gnomAD v2.1 and v4.1 records report absence rather than healthy-carrier or homozygote observations.
• Population absence cannot be converted into BS2 evidence.

Still missing

• No documented healthy adult carriers or homozygotes for this exact variant.
• No inheritance, disease-prevalence, or penetrance analysis establishing that unaffected carriers contradict disease causality.

Sources

Reasoning

No validated experimental study demonstrating that NM_001127500.2:c.3073_3082+25del has a normal effect on MET splicing, transcript expression, protein function, or a biologically relevant cellular phenotype was identified. The available SpliceAI prediction indicates possible splice impact with a max delta score of 0.943 and is not evidence of a well-established benign functional effect; therefore BS3 cannot be applied.

Evidence considered

• No publication or source in the case evidence reports a validated benign functional assay for NM_001127500.2:c.3073_3082+25del.
• SpliceAI reports a maximum delta score of 0.943 and predicts possible splice impact; this does not support BS3.

Still missing

• A validated assay demonstrating preserved MET splicing, transcript expression, protein activity, or relevant cellular function is needed.
• Assay controls, reproducibility, and quantitative evidence supporting a normal functional effect are unavailable.

Sources

Reasoning

No unaffected, phenotype-relevant relatives were tested or reported as lacking the variant, and no informative non-segregation analysis was provided. Therefore, BS4 cannot be assessed under the generic ACMG/AMP framework.

Rule

Generic ACMG/AMP BS4 supports benignity when a variant fails to segregate with disease in an informative family analysis or is present in unaffected relatives; age-dependent penetrance and phenocopies must be considered.

Evidence considered

• The available case evidence contains no tested unaffected relatives, negative familial genotypes, or informative non-segregation observations.
• The MET case has no applicable VCEP/CSPEC specification; generic ACMG/AMP criteria are therefore the fallback, but no non-segregation dataset is available.

Still missing

• Pedigree and phenotype characterization of unaffected relatives.
• Genotype results for informative unaffected relatives.
• Assessment of age-related penetrance and phenocopies before interpreting non-segregation.

Reasoning

No MET-specific VCEP or gene-specific framework was retrieved, so the generic ACMG/AMP framework applies. The available case evidence documents only the variant description and database/prediction results; it contains no observation of this variant in trans with a pathogenic or likely pathogenic variant, no cis/trans phase information, and no inheritance or affected-status data. Therefore, BP2 cannot be assessed.

Rule

BP2 requires observation of the variant in trans with a pathogenic or likely pathogenic variant in a fully penetrant recessive disorder, or in cis with a pathogenic variant; the required observations are absent.

Evidence considered

• The case evidence provides no cis/trans phase, pathogenic-partner, affected-status, family-testing, or inheritance observations relevant to BP2.
• No applicable MET-specific VCEP framework was retrieved; generic ACMG/AMP assessment is therefore required.

Still missing

• Observation of the variant with a pathogenic or likely pathogenic variant in trans is not documented.
• Cis/trans phase information is not documented.
• Affected status and inheritance information are not documented.

Reasoning

No evidence documents a confirmed alternative molecular diagnosis explaining the patient's phenotype or establishes that this exact MET variant is in a patient with a phenotype attributable to another pathogenic variant. The available materials also contain no BP5-specific likelihood-ratio value or governing VCEP threshold, so BP5 cannot be assessed.

Rule

BP5 requires a confirmed alternative molecular cause that better explains the phenotype; a quantitative BP5 rule cannot be applied without the governing criterion-specific operator and threshold.

Evidence considered

• The case materials provide no alternative pathogenic variant, alternative molecular diagnosis, or BP5-specific quantitative evidence.

Still missing

• A confirmed alternative molecular diagnosis and any applicable BP5-specific threshold are unavailable.