FGFR2 c.2383G>A, p.(Asp795Asn)

Reasoning

PM2 is met at supporting strength. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with no reported population allele frequency or homozygote observation in the case evidence bundle. This supports rarity in reference populations and is consistent with the generic PM2 criterion.

Rule

Generic PM2: absent from or nearly absent from population databases, subject to applicable disease-specific specifications.

Evidence considered

• The case evidence bundle reports NM_000141.4:c.2383G>A as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
• No alternate allele frequency or homozygote count is reported for the variant in the available population datasets.
• Generic PM2 supports a variant that is absent from or nearly absent from population databases; no FGFR2-specific population rule was retrieved.

Still missing

• The case bundle does not provide dataset-specific total allele counts, coverage metrics, or ancestry-specific denominators; these would be useful for a more granular rarity assessment.

Sources

Reasoning

No ClinGen VCEP/CSPEC framework is available for FGFR2 in this case (cspec.found=false, framework_mode=generic_acmg), so generic ACMG/AMP computational-evidence rules with published calibrated thresholds apply. This is a missense variant (NP_000132.3:p.(Asp795Asn)); no synonymous consequence, so BP7 is not applicable. REVEL score = 0.522, which falls below the ClinGen SVI-recommended REVEL PP3_Supporting threshold of >=0.644 (Pejaver et al. 2022, PMID:36413997), so REVEL does not support PP3 at any strength. SpliceAI max delta score = 0.103 (DS_AL, from spliceai source), which falls below the ClinGen SVI SpliceAI PP3 threshold of >=0.2 (Walker et al. 2023, PMID:37352857), so SpliceAI does not support a splice-altering prediction either. A local BayesDel score (-0.1813) was retrieved for this variant, but per this pipeline's evidence-quality policy no verified published calibration threshold/publication for BayesDel is available, so it is treated as not_available and not used to adjudicate PP3. With no calibrated in-silico predictor crossing a supporting (or higher) threshold in the deleterious direction, PP3 is not met.

Rule

Generic ACMG/AMP PP3 (computational predictor supports deleterious effect), using ClinGen SVI-calibrated REVEL and SpliceAI thresholds

Evidence considered

• REVEL score 0.522 for NM_000141.4:c.2383G>A (NP_000132.3:p.(Asp795Asn)), from local REVEL v1.3 lookup (source_registry key 'revel'); below the >=0.644 PP3_Supporting threshold established in Pejaver V et al., Am J Hum Genet 2022;109(12):2163-2177, PMID:36413997 (ClinGen SVI calibration of REVEL for PP3/BP4).
• SpliceAI scores for this variant: DS_AG=0.036, DS_AL=0.103, DS_DG=0.006, DS_DL=0.0 (max delta = 0.103), from SpliceAI Lookup (source_registry key 'spliceai'); below the >=0.2 PP3 threshold recommended by Walker LC et al., Am J Hum Genet 2023;110(7):1046-1067, PMID:37352857 (ClinGen SVI Splicing Subgroup recommendations).
• Local BayesDel score -0.1813 was found (source_registry key 'bayesdel') but is excluded from PP3 adjudication because no named, citable publication with a verified threshold for this BayesDel model/version is available to this pipeline.

Still missing

• No gene-specific VCEP/CSPEC PP3/BP4 lookup table was available for FGFR2 to override generic thresholds.
• BayesDel score exists (-0.1813) but has no verified published calibration/threshold citation available to this pipeline, so it could not be used for PP3 assessment.

Sources

Reasoning

PP5 is not met. The exact variant NM_000141.4:c.2383G>A is reported as absent from ClinVar, with no expert-panel classification. No qualifying exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion is available.

Rule

Apply PP5 only when an exact-variant ClinVar expert-panel classification is Pathogenic or Likely pathogenic; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• The exact-variant ClinVar search returned no result; the submission audit records zero submissions, no expert panels, and the sentence 'This variant is absent from ClinVar.'
• Ordinary laboratory submissions, aggregate ClinVar labels, non-expert assertions, and gene-level or other database classifications were not used to trigger PP5.

Sources

Reasoning

BA1 is not met. The variant is absent from the available gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 records, so no population allele frequency approaches the generic standalone benign threshold of greater than 5%.

Rule

Generic BA1: allele frequency greater than 5%.

Evidence considered

• The case evidence bundle reports NM_000141.4:c.2383G>A (FGFR2 p.Asp795Asn) as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
• Under the generic ACMG/AMP fallback, BA1 requires an allele frequency greater than 5%; an absent variant cannot meet that threshold.
• No applicable FGFR2-specific VCEP or gene-specific framework was retrieved, so the generic ACMG/AMP fallback was used.

Sources

Reasoning

Under the same generic ACMG/AMP framework (no FGFR2 VCEP/CSPEC available), REVEL score = 0.522 exceeds the ClinGen SVI-recommended REVEL BP4_Supporting threshold of <=0.290 (Pejaver et al. 2022, PMID:36413997), so REVEL does not support a benign computational prediction. SpliceAI max delta score = 0.103 is below the >=0.2 PP3 threshold but does not fall below the <0.1 threshold ClinGen SVI recommends for confidently predicting no splicing impact (Walker et al. 2023, PMID:37352857); it sits in the indeterminate zone (0.1-0.2), so SpliceAI likewise does not support BP4. BayesDel is treated as not_available for the same calibration-gap reason noted under PP3. With REVEL actively falling in an indeterminate/non-benign zone and SpliceAI also indeterminate, BP4 is not met.

Rule

Generic ACMG/AMP BP4 (computational predictor supports benign effect), using ClinGen SVI-calibrated REVEL and SpliceAI thresholds

Evidence considered

• REVEL score 0.522 for NM_000141.4:c.2383G>A, from local REVEL v1.3 lookup (source_registry key 'revel'); above the <=0.290 BP4_Supporting threshold from Pejaver V et al., Am J Hum Genet 2022;109(12):2163-2177, PMID:36413997.
• SpliceAI max delta score 0.103 (DS_AL), from SpliceAI Lookup (source_registry key 'spliceai'); falls in the indeterminate zone relative to the <0.1 BP4 no-impact threshold recommended by Walker LC et al., Am J Hum Genet 2023;110(7):1046-1067, PMID:37352857.
• Local BayesDel score -0.1813 was found (source_registry key 'bayesdel') but is excluded from BP4 adjudication because no named, citable publication with a verified threshold for this BayesDel model/version is available to this pipeline.

Still missing

• SpliceAI max delta of 0.103 sits in the indeterminate zone between the SVI BP4 no-impact threshold (<0.1) and PP3 threshold (>=0.2), preventing a confident benign call from splicing evidence alone.
• No gene-specific VCEP/CSPEC PP3/BP4 lookup table was available for FGFR2 to override generic thresholds.
• BayesDel score exists (-0.1813) but has no verified published calibration/threshold citation available to this pipeline, so it could not be used for BP4 assessment.

Sources

Reasoning

BP6 is not met. The exact variant NM_000141.4:c.2383G>A is reported as absent from ClinVar, with no expert-panel classification. No qualifying exact-variant ClinVar expert-panel Benign or Likely benign assertion is available.

Rule

Apply BP6 only when an exact-variant ClinVar expert-panel classification is Benign or Likely benign; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• The exact-variant ClinVar search returned no result; the submission audit records zero submissions, no expert panels, and the sentence 'This variant is absent from ClinVar.'
• Ordinary laboratory submissions, aggregate ClinVar labels, non-expert assertions, and gene-level or other database classifications were not used to trigger BP6.

Sources

Reasoning

PS1 requires a different nucleotide change at this same codon that produces the identical amino acid change (p.Asp795Asn) and has been established as pathogenic. No CSPEC/VCEP framework is available for FGFR2 (cspec.found = false, gene_vcep_dir = null), so the generic ACMG PS1 definition applies. ClinVar was queried directly for this variant and returned no result (search_status = no_result, evidence_sentence: 'This variant is absent from ClinVar'), and no dedicated PS1 comparator search (alternate codon-level nucleotide changes yielding the same p.Asp795Asn) was performed or returned in this bundle.

Evidence considered

• ClinVar direct query for FGFR2 c.2383G>A returned search_status = no_result / found = false, evidence_sentence: 'This variant is absent from ClinVar.'
• No cspec/VCEP framework found for FGFR2 (case_summary.json cspec.found = false), so generic ACMG/AMP PS1 semantics would apply if comparator data were available.

Still missing

• No PS1-specific search was performed for other nucleotide substitutions at codon 795 that produce the same p.Asp795Asn change and have an established pathogenic classification.
• ClinVar has no entry for this variant itself, so a same-codon PS1 comparator cannot be confirmed from the data provided.

Sources

Reasoning

No proband-level de novo evidence is provided. The case-evidence bundle contains no parental testing results, maternity/paternity confirmation, trio sequencing data, or validated absence of the variant in both parents; therefore PS2 cannot be assessed.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history; stronger use requires confirmed maternity/paternity and absence of the variant in both parents.

Evidence considered

• The consolidated case-evidence bundle identifies the variant as NM_000141.4:c.2383G>A (FGFR2 p.Asp795Asn) but provides no proband, parent, trio, de novo, or maternity/paternity evidence.
• No applicable FGFR2-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback is therefore used, but its PS2 requirement cannot be met without documented de novo testing evidence.

Still missing

• Proband testing context and phenotype are not provided.
• Parental genotypes and testing methodology are not provided.
• Maternity/paternity confirmation and assessment for parental mosaicism are not provided.

Reasoning

No governing VCEP/CSPEC is available for FGFR2 (cspec.found=false; final_classification_framework.found=false, generic ACMG fallback in use), so no gene-specific PS3 functional assay framework applies. The consolidated evidence bundle (case_summary, source_registry, literature_pass, vcep_materials, fulltext_map) contains no functional/biochemical assay data for NM_000141.4:c.2383G>A (p.Asp795Asn) -- no kinase activity, phosphorylation, signaling, cell proliferation, or other validated functional study results were found in any prefetched or literature source. The identified PVS1-context literature (sperm sequencing, acne syndromes, neurocutaneous syndrome case reports, osteoporosis case report, Kirner's deformity pedigree) is gene/disease-context literature, not variant-specific functional assay data, and none of it reports a validated functional assay for this variant.

Still missing

• No validated in vitro or in vivo functional assay (e.g., kinase activity, receptor dimerization/phosphorylation, cell-based signaling assay) for NM_000141.4:c.2383G>A (p.Asp795Asn) was found in the evidence bundle or screened literature.
• No gene-specific FGFR2 VCEP PS3/BS3 assay-validation framework (assay controls, effect-size thresholds, strength calibration) was available to apply.

Reasoning

No case-control cohort, affected-case count, control comparison, or statistically interpretable enrichment data for NM_000141.4:c.2383G>A were available. PS4 therefore cannot be assessed.

Rule

Generic ACMG/AMP PS4 requires significantly increased prevalence of the variant in affected individuals compared with controls; no applicable FGFR2-specific VCEP framework was retrieved.

Evidence considered

• The consolidated evidence bundle contains no case-control study, phenotype cohort, or variant-specific prevalence/enrichment data for NM_000141.4:c.2383G>A.

Still missing

• Variant-specific affected-case count and ascertainment details
• Appropriate control cohort and comparison data
• Case-control enrichment statistics or an applicable validated PS4 rule

Reasoning

PM1 requires the variant to fall in a mutational hotspot or well-established functional domain without benign variation. No CSPEC/VCEP framework exists for FGFR2 in this case. The bundle's only hotspot-relevant lookup, cancerhotspots.org, returned no_result / found = false for FGFR2 D795 ('This variant does not lie in a statistically significant hotspot'). No UniProt/Pfam domain boundary annotation, kinase-domain coordinate data, or residue-level constraint/benign-variation-density data for residue 795 was retrieved anywhere in this bundle, so PM1's functional-domain prong cannot be verified from the provided evidence, only from general external knowledge which is not permissible to cite without a grounded source in this bundle.

Evidence considered

• cancerhotspots.org query for 'FGFR2 D795' returned search_status = no_result / found = false with evidence_sentence 'This variant does not lie in a statistically significant hotspot' (this is a somatic cancer hotspot resource, not a germline domain/constraint source, and is the only hotspot-adjacent lookup present in the bundle).

Still missing

• No structural/domain annotation (e.g., UniProt kinase domain boundaries for FGFR2 NP_000132.3) was retrieved to confirm whether residue 795 lies within the tyrosine kinase domain.
• No hotspot or regional missense-density/constraint data (beyond the negative cancerhotspots.org somatic-cancer lookup) was collected to assess PM1 under a generic ACMG framework.

Reasoning

No applicable FGFR2-specific VCEP framework was retrieved, so the generic ACMG/AMP PM3 concept applies. The case-evidence bundle contains no affected-proband observations, phase information, inheritance data, or documented pathogenic/likely pathogenic variant in trans; therefore PM3 cannot be assessed.

Rule

Generic ACMG/AMP PM3: pathogenicity evidence from a recessive disorder in which the variant is observed in trans with a pathogenic variant, with strength depending on the number and quality of informative observations.

Evidence considered

• The governing framework materials report that no FGFR2-specific CSPEC/VCEP specification was found and that generic ACMG/AMP fallback is being used.
• The consolidated case-evidence bundle reports no literature PMIDs and contains no family-level observations, affected-proband data, phase data, or inherited second-variant information relevant to PM3.

Still missing

• Affected-proband case data are not provided.
• Phase and inheritance information are not provided.
• No pathogenic or likely pathogenic variant in trans is documented.

Reasoning

PM5 requires a different missense change at the same residue (D795) that has been established as pathogenic, distinct from the observed p.Asp795Asn. The dedicated pm5_candidates.json artifact explicitly reports eligible_for_classic_pm5_search = false and pm5_mode = 'unknown', with the stated reason 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting.' Zero candidates were collected (total_candidates_seen = 0, same_residue_candidates = 0), and its own recommendation instructs not to apply PM5 from this artifact alone.

Evidence considered

• pm5_candidates.json: pm5_mode='unknown', eligible_for_classic_pm5_search=false, candidate_summary.total_candidates_seen=0, same_residue_candidates=0, recommendation.level='not_applicable' with instruction 'Review whether any collected same-residue comparator variants satisfy the governing PM5 rule; do not apply PM5 from this artifact alone.'

Still missing

• No same-residue comparator missense variant search was actually executed; the pm5_candidates artifact explicitly deferred this search rather than returning negative results.
• A manual ClinVar/literature search for other p.Asp795X missense changes at codon 795 has not been performed in this bundle.

Sources

Reasoning

No unconfirmed de novo observations are reported for this variant. There are no parental testing results, family-history details, or case reports documenting a suspected de novo occurrence; therefore PM6 cannot be assessed.

Rule

Generic ACMG/AMP PM6: assumed de novo, but without confirmation of maternity and/or paternity, in a patient with the disease and no family history.

Evidence considered

• The consolidated case-evidence bundle reports no literature PMIDs and contains no case-level de novo or family data for NM_000141.4:c.2383G>A.
• Generic ACMG/AMP PM6 requires a credible but incompletely verified de novo occurrence; no such observation is documented in the available evidence.

Still missing

• Evidence of a suspected de novo occurrence is absent.
• Parental testing quality and results are absent.
• Family history and phenotype details for any reported proband are absent.

Reasoning

No affected relatives, unaffected relatives, pedigrees, genotype data, phenotype assessments, or informative meioses are provided. Segregation evidence cannot be evaluated, so PP1 is not assessed.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Evidence considered

• The consolidated case-evidence bundle contains no pedigree, familial genotype, familial phenotype, segregation, or meiosis information for the variant.
• Generic ACMG/AMP PP1 requires cosegregation with disease in multiple affected family members; that evidence is unavailable.

Still missing

• Pedigree and family structure are not provided.
• Genotypes and phenotypes of informative relatives are not provided.
• Number of informative meioses and segregation probability cannot be determined.

Reasoning

PP2 requires both (a) missense variants being a common/established mechanism of disease for the gene and (b) a low rate of benign missense variation in the gene. No FGFR2 CSPEC/VCEP framework is available (generic ACMG fallback). The literature gathered for this case's PVS1 gene-context step supports part (a): a full-text-reviewed paper explicitly states 'Heterozygous activating non-mosaic germline variants in FGFR2 have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses and skeletal dysplasia syndromes,' consistent with well-documented activating missense as a disease mechanism for FGFR2. However, no gnomAD missense constraint metric (e.g., missense Z-score/o.e.), ClinVar benign-missense-rate statistic, or other quantitative source addressing part (b), the rate of benign missense variation in FGFR2, was retrieved anywhere in this bundle. Without grounded data for the benign-missense-rate prong, PP2 cannot be confidently scored either met or not_met under the generic ACMG framework.

Evidence considered

• pvs1_gene_context.json supporting paper (PMID:38265560, 'Expansion of the complex genotypic and phenotypic spectrum of FGFR2-associated neurocutaneous syndromes'), abstract text: 'Heterozygous activating non-mosaic germline variants in FGFR2 have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses and skeletal dysplasia syndromes,' supporting missense/activating variants as an established FGFR2 disease mechanism.
• No gnomAD missense constraint or benign-missense-rate data was found anywhere in the bundle for FGFR2, so the second required prong of PP2 remains unverified.

Still missing

• No gnomAD constraint metric (missense Z-score / observed:expected ratio) or ClinVar benign-missense-rate summary for FGFR2 was retrieved to evaluate the 'low rate of benign missense variation' prong of PP2.
• No formal cspec/VCEP PP2 rule exists for FGFR2 in this case; a generic ACMG determination would still require the missing constraint data above.

Sources

Reasoning

No patient-level phenotype, clinical diagnosis, or disease-specific phenotype description was provided for the individual carrying NM_000141.4:c.2383G>A. Phenotype specificity cannot be evaluated.

Rule

Generic ACMG/AMP PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single-gene etiology; no applicable FGFR2-specific VCEP framework was retrieved.

Evidence considered

• The case summary and consolidated evidence bundle provide variant normalization and database results but no patient phenotype or phenotype-specific diagnostic assessment.

Still missing

• Patient phenotype and clinical diagnosis
• Evidence that the phenotype is highly specific for an FGFR2-associated disorder
• Relevant differential-diagnosis information

Reasoning

BS1 cannot be applied from the available evidence. The variant is absent from the available population datasets, but the case bundle provides no disease-specific prevalence, penetrance, inheritance, age-of-onset, or maximum credible allele-frequency model for the relevant FGFR2-associated disorder. Consequently, there is no documented disorder-specific expected-frequency threshold against which to assess BS1.

Rule

Generic BS1: allele frequency greater than expected for the disorder; application requires a disease-specific expected-frequency threshold.

Evidence considered

• The case evidence bundle reports the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
• Generic BS1 requires an allele frequency greater than expected for the specific disorder; no disorder-specific frequency threshold or prevalence/penetrance model is available in this case.
• No applicable FGFR2-specific VCEP or gene-specific framework was retrieved, so the generic ACMG/AMP fallback was used.

Still missing

• A documented disease-specific prevalence and penetrance model is needed to establish the maximum credible allele frequency for BS1.
• The relevant FGFR2-associated disorder and its inheritance, penetrance, and age-of-onset parameters are not specified in the case bundle.
• Absence from population databases does not itself demonstrate that a frequency is greater than expected for the disorder.

Sources

Reasoning

BS2 is not assessed. The available population records report the variant as absent and therefore provide no homozygous observations. However, the case bundle contains no qualifying healthy-adult cohort, individual-level phenotype information, age information, or clinically documented homozygous individuals. Absence of homozygotes in population databases does not establish the BS2 healthy-individual criterion.

Rule

Generic BS2: observation in healthy adult individuals, including homozygotes when relevant to the inheritance model; population absence alone is insufficient.

Evidence considered

• The case evidence bundle reports the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so no population homozygote count is available.
• Generic BS2 requires observation in healthy adults, including homozygotes when relevant; absence of a homozygote observation is not positive BS2 evidence.
• No qualifying healthy-individual or homozygote phenotype data are available in the case bundle.

Still missing

• No qualifying healthy-adult cohort or individual-level clinical information was provided.
• No clinically documented homozygous individuals, including age and phenotype status, were provided.
• The inheritance model and disease-specific implications of homozygosity are not documented in the case bundle.

Sources

Reasoning

No governing VCEP/CSPEC is available for FGFR2 (cspec.found=false; generic ACMG fallback in use), so no gene-specific BS3 framework applies. The consolidated evidence bundle contains no functional assay data of any kind (benign-supporting or otherwise) for this variant -- no reports showing normal/wild-type-like functional activity for NM_000141.4:c.2383G>A (p.Asp795Asn) were identified in prefetch, literature_pass, or full-text sources.

Still missing

• No functional assay data (of any directional result) exists in the evidence bundle for this variant, so a benign-supportive functional finding cannot be evaluated.
• No gene-specific FGFR2 VCEP BS3 assay-validation framework was available to apply.

Reasoning

No affected-family phenotype data or genotypes from informative unaffected relatives are available. Non-segregation cannot be established, so BS4 is not assessed.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected members of a family.

Evidence considered

• The consolidated case-evidence bundle contains no family pedigree, unaffected-relative testing, or non-segregation observations for NM_000141.4:c.2383G>A.
• Generic ACMG/AMP BS4 requires lack of segregation in affected members of a family; no such family data are available.

Still missing

• Phenotype assessments of relatives are not provided.
• Genotypes of clinically unaffected relatives are not provided.
• Family structure, age-related penetrance considerations, and informativeness of non-segregation are unknown.

Reasoning

No applicable FGFR2-specific VCEP framework was retrieved, so the generic ACMG/AMP BP2 concept applies. The case-evidence bundle contains no phase-resolved observation of the variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant for a recessive disorder; therefore BP2 cannot be assessed.

Rule

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

Evidence considered

• The governing framework materials report that no FGFR2-specific CSPEC/VCEP specification was found and that generic ACMG/AMP fallback is being used.
• The consolidated case-evidence bundle reports no literature PMIDs and contains no phase-resolved allelic observations or pathogenic comparator variant relevant to BP2.

Still missing

• Phase information is not provided.
• Inheritance mode and relevant disease model are not documented for this case.
• No pathogenic or likely pathogenic comparator variant in cis or trans is documented.

Reasoning

No patient-level phenotype, molecular diagnosis, or independent pathogenic variant explaining the relevant phenotype was available. The absence of such information prevents assessment of whether an alternate molecular basis accounts for the phenotype.

Rule

Generic ACMG/AMP BP5 requires an alternate molecular basis that explains the patient's phenotype; no applicable FGFR2-specific VCEP framework was retrieved.

Evidence considered

• The consolidated evidence bundle contains no alternate molecular diagnosis or phenotype-linked finding that could establish an alternate explanation for the case.

Still missing

• Patient phenotype and indication
• Independent molecular diagnosis or pathogenic variant explaining the phenotype
• Evidence that the alternate molecular basis accounts for the observed phenotype