DDX41 c.1479C>T, p.(Ser493=)

Reasoning

BS1 (strong benign) is met: the allele frequency in control populations is greater than expected for the disorder (ACMG/AMP 2015, PMID:25741868). This lab's documented generic-fallback operating threshold is AF > 0.3% on the maximum population AF basis. The variant is East Asian-enriched: gnomAD v4.1 EAS AF 0.709% (318/44,870 alleles, 2 homozygotes), grpmax FAF 0.645%; gnomAD v2.1 EAS AF 0.847% (169/19,954), grpmax FAF 0.760%; gnomAD-Canada v1.0 EAS AF 1.495% (20/1,338, 1 homozygote). All exceed the 0.3% threshold. DDX41-related hematologic malignancy predisposition syndrome (MONDO:0014809) is a rare autosomal-dominant, adult-onset disorder with incomplete, age-dependent penetrance, so the expected frequency of a disease-causing allele is far below 0.3%; this variant's frequency far exceeds that expectation. The observation of multiple homozygotes (2 in gnomAD v4.1, 1 in gnomAD-Canada, all EAS) is consistent with a common benign polymorphism rather than a fully penetrant disease allele. BS1 applied at strong strength.

Rule

generic_acmg_fallback: BS1 AF > 0.3% (lab operating threshold, max population AF basis)

Evidence considered

• gnomAD v4.1: EAS AF 0.00708714 (318/44,870 alleles, 2 homozygotes); grpmax FAF 0.00644595; total AF 0.000284975 (460/1,614,176)
• gnomAD v2.1: EAS AF 0.00846948 (169/19,954 alleles, 0 homozygotes); grpmax FAF 0.00759882; total AF 0.000717867 (203/282,782)
• gnomAD-Canada v1.0: EAS AF 0.0149477 (20/1,338 alleles, 1 homozygote); total AF 0.0014658 (27/18,420)
• EAS maximum population AF (0.71-0.85% in gnomAD v2/v4; grpmax FAF 0.65-0.76%) exceeds this lab's generic-fallback BS1 threshold of 0.3%
• DDX41-related hematologic malignancy predisposition is a rare autosomal-dominant adult-onset disorder (MDS/AML typically presenting in later adulthood) with incomplete, age-dependent penetrance; the expected allele frequency for a disease allele is far below 0.3% (general domain knowledge; no variant-specific literature required for this AF-based criterion)
• ACMG/AMP 2015 (PMID:25741868): 'an allele frequency in a control population that is greater than expected for the disorder (Table 6) is considered strong support for a benign interpretation for a rare Mendelian disorder (BS1)'

Still missing

• VCEP-specific BS1 threshold for DDX41 (ClinGen Myeloid Malignancy EP v1.0) not retrievable - empty rules payload; generic 0.3% max-population-AF threshold applied, confirm with human review
• BS1 met only on the maximum population AF basis (EAS); overall AF (0.03-0.07%) is below the threshold

Sources

Reasoning

BP7 is met (supporting). (1) The variant is synonymous: NM_016222.2:c.1479C>T, NP_057306.2:p.(Ser493=), exon 14, annotated 'synonymous_variant' by VEP in gnomAD-Canada. (2) Splicing prediction algorithms predict no impact: SpliceAI max delta score 0.015 (DS_AG 0.015, DS_AL 0.014, DS_DG 0.003, DS_DL 0.002), well below the recommended 0.2 clinical threshold for splice-altering prediction (Jaganathan et al. 2019, PMID 30661751); nearest splice-site distances (DP_AG -28, DP_AL -150, DP_DG 220, DP_DL 264) place the variant outside the splice consensus and no new splice site creation is predicted. (3) The nucleotide is not highly conserved: the variant is a common East Asian polymorphism in gnomAD v4.1 (EAS AF 0.00709, 318/44870 alleles, 2 homozygotes) and gnomAD v2.1 (EAS AF 0.00847, 169/19954). All components of BP7 are satisfied.

Rule

BP7: A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved (ACMG/AMP 2015, PMID 25741868). Supporting strength by definition.

Evidence considered

• SpliceAI Lookup (source key: spliceai): max delta score 0.015 (DS_AG 0.015, DS_AL 0.014, DS_DG 0.003, DS_DL 0.002) for NM_016222.2:c.1479C>T, below the recommended 0.2 clinical threshold for predicting splice alteration (Jaganathan et al. 2019, Nature Genetics, PMID 30661751); nearest splice-site distances (DP_AG -28, DP_AL -150, DP_DG 220, DP_DL 264) place the variant outside the splice consensus, and no new acceptor/donor gain is predicted.
• The variant is synonymous: NM_016222.2:c.1479C>T, NP_057306.2:p.(Ser493=), exon 14 of DDX41; gnomAD-Canada VEP annotation is 'synonymous_variant' (source key: gnomad_canada).
• Nucleotide not highly conserved: gnomAD v4.1 (source key: gnomad_v4) total AF 0.000285 with East Asian AF 0.00709 (318/44870 alleles, 2 homozygotes); gnomAD v2.1 (source key: gnomad_v2) East Asian AF 0.00847 (169/19954 alleles, 0 homozygotes). A common East Asian polymorphism with observed homozygotes indicates the position tolerates variation, satisfying the BP7 non-conservation component.
• No DDX41 VCEP-specific BP7 rule exists (cspec criteria payload empty; source key: cspec; vcep_db/DDX41 criteria.json empty), so the generic ACMG/AMP 2015 BP7 definition (PMID 25741868) applies.

Still missing

• Direct conservation scores (e.g., PhyloP/PhastCons) were not present in the case bundle; the non-conservation component of BP7 was supported by the variant being a common East Asian polymorphism (gnomAD v4.1 EAS AF 0.71% with 2 observed homozygotes) rather than by a direct conservation metric.

Sources

Reasoning

No case-control or case-series enrichment data for DDX41 c.1479C>T exist in any reviewed source. ClinVar VCV000726954 carries only laboratory classifications with no cohort data; the literature pass identified no publication mentioning this variant; COSMIC reports 2 somatic occurrences, which are somatic tumor observations, not germline case-control enrichment. Population context is inconsistent with strong pathogenic enrichment: the synonymous variant is common in East Asians (gnomAD v4.1 EAS AF 0.7087%, 2 homozygotes; gnomAD v2.1 EAS AF 0.8469%). PS4 is therefore not met under the generic ACMG/AMP 2015 rule (DDX41 CSPEC ruleset is empty, so no gene-specific PS4 specification applies).

Rule

ACMG/AMP 2015 PS4 (generic fallback; PMID:25741868 via generic_acmg_combination_rules): the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (case-control enrichment; strength strong, adjustable per SVI guidance).

Evidence considered

• Reviewed ClinVar VCV000726954: 4 germline clinical-testing submissions (Benign x3, Likely benign x1); the record contains no case-control or cohort enrichment data and has 0 expert-panel submissions.
• literature_pass.json returned no publication that mentions c.1479C>T; all 7 retrieved PMIDs are newborn-screening, carrier-screening, or guideline background papers unrelated to DDX41 and were not used.
• COSMIC lists 2 somatic occurrences (COSV57251228); somatic tumor observations are not germline case-control enrichment evidence and 'cosmic' is not a registered source_registry key, so this is narrative context only, not a citable evidence ref.
• Population context: gnomAD v4.1 total AF 0.0285% with EAS AF 0.7087% (318/44870 alleles, 2 homozygotes); gnomAD v2.1 total AF 0.0718% with EAS AF 0.8469% (169/19954 alleles, 0 homozygotes) — a comparatively common East Asian synonymous variant, inconsistent with a strong pathogenic enrichment signal.
• Generic ACMG/AMP 2015 PS4 (prevalence of the variant in affected individuals significantly increased compared with prevalence in controls) applied because the governing DDX41 CSPEC v1.0 specification was retrieved with an empty ruleset (criteria: [], rule_payload: {}, framework_complete: false).

Still missing

• No case-control or case-series study reporting prevalence of c.1479C>T in affected individuals versus controls was identified; such a study would be required to revisit PS4.

Sources

Reasoning

PM2 (moderate pathogenic) is not met. PM2 requires the variant to be absent from, or at extremely low frequency in, a large race-matched control population (ACMG/AMP 2015, PMID:25741868). This lab's documented generic-fallback operating threshold is AF < 0.1% on the maximum population AF basis. Although the overall AF is low (gnomAD v4.1 total AF 0.0285%; gnomAD v2.1 0.0718%), the variant is present in East Asians at AF 0.709% (gnomAD v4.1, 318/44,870) and 0.847% (gnomAD v2.1, 169/19,954), with grpmax FAF 0.645-0.760%, and is observed in 2 homozygotes in gnomAD v4.1. Applying PM2 on the overall AF while the variant is enriched in a specific ancestry group would be a population-threshold artifact; the maximum population AF is the appropriate basis, and it far exceeds any PM2 threshold. PM2 is not met.

Rule

generic_acmg_fallback: PM2 AF < 0.1% (lab operating threshold, max population AF basis) - not met

Evidence considered

• gnomAD v4.1: EAS AF 0.00708714 (318/44,870 alleles, 2 homozygotes) - far above the 0.1% PM2 threshold; grpmax FAF 0.00644595
• gnomAD v2.1: EAS AF 0.00846948 (169/19,954 alleles) - far above the 0.1% PM2 threshold; grpmax FAF 0.00759882
• gnomAD-Canada v1.0: EAS AF 0.0149477 (20/1,338, 1 homozygote) - corroborating EAS enrichment
• Overall AF (0.0285% v4 / 0.0718% v2) is below 0.1%, but PM2 must be evaluated on the maximum population AF, not the overall AF, for variants with ancestry-specific enrichment; on that basis PM2 is not met
• This lab's documented generic-fallback operating threshold for PM2 is AF < 0.1% (non-VCEP), applied on maximum population AF
• ACMG/AMP 2015 (PMID:25741868): 'If a variant is absent from (or below the expected carrier frequency if recessive) a large general population or a control cohort (>1000 individuals) and the population is race-matched to the patient harboring the identified variant, then this observation can be considered a moderate piece of evidence for pathogenicity (PM2)'

Sources

Reasoning

PP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene or gene product. The variant is synonymous (NP_057306.2:p.(Ser493=)), so the missense in-silico path (REVEL/BayesDel/aGVGD) does not apply, and no such scores were retrievable (REVEL and BayesDel lookups found=false). On the splice path, SpliceAI predicts no impact: max delta score 0.015 (DS_AG 0.015, DS_AL 0.014, DS_DG 0.003, DS_DL 0.002), far below the recommended 0.2 clinical cutoff for splice-altering prediction (Jaganathan et al. 2019, PMID 30661751). There is therefore no computational evidence of a deleterious effect, and PP3 is not met.

Rule

PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (ACMG/AMP 2015, PMID 25741868). No DDX41 VCEP-specific PP3 calibration available (cspec criteria payload empty), so the generic rule governs.

Evidence considered

• SpliceAI Lookup (source key: spliceai) returned max delta score 0.015 (DS_AG 0.015, DS_AL 0.014, DS_DG 0.003, DS_DL 0.002) for NM_016222.2:c.1479C>T; all four delta scores are far below the recommended 0.2 clinical cutoff for splice-altering prediction (Jaganathan et al. 2019, Nature Genetics, PMID 30661751), so no computational evidence of splice impact exists.
• REVEL and BayesDel local lookups returned no scores (found=false); these missense-oriented predictors are not applicable to a synonymous variant, and no verified published threshold is available to this pipeline for BayesDel.
• Generic ACMG/AMP 2015 definition of PP3 (PMID 25741868) applied because the ClinGen Myeloid Malignancy VCEP DDX41 v1.0 cspec (source key: cspec) contains no gene-specific PP3 specification (criteria payload empty).

Still missing

• REVEL and BayesDel scores were not retrievable (local lookups found=false); neither is applicable to a synonymous variant, so the determination rests on the splice path, where SpliceAI clearly predicts no impact.

Sources

Reasoning

PP5 requires an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic. ClinVar VCV000726954 contains 4 submissions, all from routine clinical-testing laboratories (University of Chicago GSL, PreventionGenetics, Ambry Genetics, Labcorp/Invitae); the submission audit reports expert_panel_submissions = 0 and the aggregate classification is Benign/Likely benign, not Pathogenic. No expert-panel Pathogenic/Likely pathogenic classification exists for this variant, so PP5 is not met.

Rule

ACMG/AMP 2015 PP5 (generic definition; PMID:25741868): reputable source recently reports variant as pathogenic but evidence is not available for independent evaluation — pipeline policy restricts application to an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification (supporting).

Evidence considered

• ClinVar submission audit (prefetch.json/clinvar_submission_audit): submissions_total 4, expert_panel_submissions 0, usable_for_criterion_leads 0; all submissions are clinical-testing laboratories, none is an expert panel.
• Aggregate ClinVar classification is Benign (3 clinical laboratories) and Likely benign (1 clinical laboratory) with review status 'criteria provided, multiple submitters, no conflicts' (2 stars) — this aggregate is not an expert-panel assertion and cannot support PP5.
• Policy: PP5 applies only for an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger PP5.

Still missing

• No exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification exists for c.1479C>T (0 expert-panel submissions on VCV000726954); PP5 would only be triggered by such a classification.

Sources

Reasoning

BA1 (stand-alone benign, ACMG/AMP 2015, PMID:25741868) requires an allele frequency far above what is expected for the disorder. This lab's documented generic-fallback operating threshold is AF > 1% on the maximum population AF basis. The variant NM_016222.2:c.1479C>T (p.Ser493=) is present in gnomAD v4.1 at total AF 0.0285% (460/1,614,176 alleles) with highest population AF in East Asians at 0.709% (318/44,870) and grpmax FAF 0.645%; gnomAD v2.1 total AF 0.0718% (203/282,782) with EAS AF 0.847% (169/19,954) and grpmax FAF 0.760%. The largest, best-powered dataset (gnomAD v4.1) shows a maximum subpopulation AF of 0.709%, below the 1% BA1 threshold, so BA1 is not met. The only AF estimate exceeding 1% is the small gnomAD-Canada v1.0 East Asian subset (AF 1.495%, 20/1,338 alleles), which is treated as corroborating evidence only, not decisive.

Rule

generic_acmg_fallback: BA1 AF > 1% (lab operating threshold, max population AF basis)

Evidence considered

• gnomAD v4.1: total AF 0.000284975 (460/1,614,176 alleles, 2 homozygotes); EAS AF 0.00708714 (318/44,870, 2 homozygotes); grpmax FAF 0.00644595 - all below 1%
• gnomAD v2.1: total AF 0.000717867 (203/282,782 alleles, 0 homozygotes); EAS AF 0.00846948 (169/19,954); grpmax FAF 0.00759882
• gnomAD-Canada v1.0: total AF 0.0014658 (27/18,420, 1 homozygote); EAS AF 0.0149477 (20/1,338, 1 homozygote) - small-sample estimate above 1%, not used as decisive for BA1
• This lab's documented generic-fallback operating threshold for BA1 is AF > 1% (non-VCEP); evaluated on maximum population AF
• ACMG/AMP 2015 (PMID:25741868): 'an allele frequency in a control population that is greater than expected for the disorder (Table 6) is considered strong support for a benign interpretation for a rare Mendelian disorder (BS1) or if over 5% then it is considered as stand-alone support (BA1)'

Still missing

• VCEP-specific BA1 threshold for DDX41 (ClinGen Myeloid Malignancy EP v1.0, CSPEC doc 1625925053) not retrievable - rules payload empty; generic 1% threshold used
• gnomAD-Canada v1.0 EAS AF 1.495% (20/1,338 alleles, small sample) crosses the lab BA1 threshold; human confirmation of the max-population-AF basis and 1% threshold is recommended

Sources

Reasoning

BP6 requires an exact-variant ClinVar expert-panel classification of Benign/Likely benign. Although the ClinVar aggregate for VCV000726954 is Benign/Likely benign (Benign x3, Likely benign x1), the submission audit reports expert_panel_submissions = 0: every submission is an ordinary clinical-testing laboratory. Per policy, ordinary laboratory submissions and aggregate ClinVar labels must never trigger BP6, so BP6 is not met despite the benign aggregate.

Rule

ACMG/AMP 2015 BP6 (generic definition; PMID:25741868): reputable source recently reports variant as benign but evidence is not available for independent evaluation — pipeline policy restricts application to an exact-variant ClinVar expert-panel Benign/Likely benign classification (supporting).

Evidence considered

• ClinVar VCV000726954 aggregate: Benign (3 clinical laboratories), Likely benign (1 clinical laboratory), review status 'criteria provided, multiple submitters, no conflicts' (2 stars); submission audit confirms expert_panel_submissions = 0.
• Submitters are routine clinical-testing laboratories (University of Chicago GSL, PreventionGenetics, Ambry Genetics, Labcorp/Invitae); none is a ClinGen or other expert panel.
• Policy: BP6 applies only for an exact-variant ClinVar expert-panel Benign/Likely benign classification; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger BP6 — therefore BP6 is not met.

Still missing

• No exact-variant ClinVar expert-panel Benign/Likely benign classification exists for c.1479C>T; the benign aggregate derives solely from routine clinical laboratory submissions and cannot trigger BP6.

Sources

Reasoning

No de novo observation exists for NM_016222.2:c.1479C>T (p.Ser493=): the case bundle contains no proband phenotype, no parental genotyping results, and no assertion of de novo origin for this variant. Per ACMG/AMP 2015 (PMID:25741868), PS2 requires a variant observed to have arisen de novo with both parental samples negative and maternity/paternity confirmed by identity testing, plus a phenotype matching the gene's disease association. None of these elements can be evaluated (no proband data at all in case_summary.json, evidence.json, prefetch.json, or literature_pass.json). The governing DDX41 Myeloid Malignancy EP specification (cspec) was identified but its ruleset text was not retrievable in this bundle (framework_complete=false, empty rule_payload), so the generic definition applies. Not assessed due to insufficient evidence.

Rule

PS2 (strong, pathogenic): De novo (maternity and paternity confirmed via identity testing) in a patient with the disease and no family history, with phenotype matching the gene's disease association; PM6 (moderate) applies when identity is assumed but not confirmed (ACMG/AMP 2015, PMID:25741868).

Evidence considered

• Governing framework: ClinGen Myeloid Malignancy EP specification for DDX41 v1.0 identified (cspec, doc 1625925053; autosomal dominant, MONDO:0014809), but vcep_materials.json reports framework_complete=false with an empty rule_payload and no retrieved files, so no VCEP-specific PS2/PM6/PP1/BS4 wording was available; generic ACMG/AMP 2015 definitions (PMID:25741868) were applied.
• No proband, parental, or family data exist anywhere in the case bundle: case_summary.json, evidence.json, prefetch.json, literature_pass.json, and source_registry.json contain no phenotype, pedigree, parental-genotype, de novo, or segregation information for this variant.
• ClinVar (clinvar) lists 4 germline laboratory submissions (3 Benign, 1 Likely benign; no expert-panel submissions, no criterion leads, 0 validated PMIDs); none report parental testing, de novo status, or family segregation, and no criterion is inferred from another source's final classification.
• Literature triage (literature_pass.json) surfaced no case reports of c.1479C>T; full-text search of the retrieved publications found no occurrence of c.1479C>T or p.Ser493.
• Population data (gnomad_v2, gnomad_v4, gnomad_canada) show the variant is common overall (AF ~0.03-0.15%) with East Asian enrichment (up to ~0.7-1.5%) and observed homozygotes; population presence provides no de novo or segregation observation and is evaluated by the population group, not this one.

Still missing

• No proband data: this is a variant-level review with no clinical phenotype or proband genotype provided.
• No parental genotyping results; de novo status (with or without confirmed maternity/paternity) cannot be established.
• DDX41 VCEP (cspec) ruleset content not retrieved; VCEP-specific PS2 wording could not be checked.

Sources

Reasoning

PS3 (well-established functional studies show a deleterious effect; Richards et al. 2015, PMID:25741868) cannot be evaluated because no variant-specific functional assay evidence exists for NM_016222.2:c.1479C>T (p.(Ser493=)) in any source in the case bundle. Governing framework: the ClinGen Myeloid Malignancy EP DDX41 v1.0 specification (cspec doc 1625925053) is present but its extracted rule payload is empty (framework_mode=unstructured_ruleset, framework_complete=false), so no gene-specific PS3/BS3 calibration is available and the generic ACMG/AMP 2015 definitions apply. Sources checked for functional content: evidence.json contains no RNA/cDNA, minigene, protein, or cellular assay results; SpliceAI (max delta 0.015) is an in-silico splicing predictor, not a functional study; OncoKB lists 'Unknown Oncogenic Effect' and is explicitly non-variant-specific; COSMIC shows only somatic occurrence (COSV57251228, n=2), which is not a functional assay; ClinVar submissions (Benign x3, Likely benign x1) are laboratory final classifications and were not used to infer functional status. The literature pass returned no publication describing functional studies of this variant (all retrieved PMIDs are ClinVar-attached background papers unrelated to DDX41 function; gene-context material contains only general DDX41 biology). With no well-established functional data of any kind, PS3 must remain not assessed.

Rule

generic_acmg_2015_PS3_BS3 (PMID:25741868); no gene-specific rule extractable from cspec payload

Evidence considered

• Framework check: cspec DDX41 Myeloid Malignancy EP v1.0 (doc 1625925053) is present but rule_payload is empty (unstructured_ruleset, framework_complete=false); no gene-specific functional criteria could be applied, so generic ACMG/AMP 2015 (PMID:25741868) governs PS3/BS3.
• ACMG/AMP 2015 (PMID:25741868) defines PS3 as well-established functional studies showing a deleterious effect and requires assay validity considerations (biological relevance, validation, reproducibility); the guideline notes mRNA-level assays (RNA/cDNA analysis, in vitro minigene splicing assays) can be highly informative for splice-relevant variants.
• evidence.json contains no functional assay results of any kind for this variant (no RNA/cDNA, minigene, protein expression, enzymatic, or cellular assays).
• SpliceAI max delta score 0.015 (DS_AG 0.015, DS_AL 0.014) predicts no significant splice impact, but this is an in-silico prediction, explicitly not a functional study, and cannot satisfy PS3 or BS3; splicing in-silico evidence belongs to BP7-type evaluation outside this group.
• OncoKB (queried DDX41/S493=) lists 'Unknown Oncogenic Effect' with is_variant_specific=false; provides no variant-specific functional data.
• COSMIC reports somatic occurrence only (COSV57251228, n=2); occurrence in somatic cancers is not functional assay evidence and was not used for PS3.
• ClinVar (VCV000726954) submissions are laboratory classifications (Benign x3, Likely benign x1) with no attached functional assay data; per policy, final classifications from other sources were not used to infer PS3/BS3.
• Literature pass (literature_pass.json) returned 7 PMIDs, none describing functional studies of c.1479C>T; gene-context full-text material contains only general DDX41 biology (splicing/snoRNA processing, cGAS-STING modulation, Ddx41 mouse models) with no variant-specific functional data.

Still missing

• No variant-specific functional assay evidence (RNA/cDNA analysis, minigene splicing assay, protein-level or cellular assay) for c.1479C>T is available in the case bundle; such data would be required to assess PS3.

Sources

Reasoning

PM6 (assumed de novo without confirmation of maternity and paternity) cannot be assessed: no parental testing results, no de novo assumption, and no proband data are reported for c.1479C>T in any bundle source. The retrieved literature contains no variant-specific case reports. Per ACMG/AMP 2015 (PMID:25741868), PM6 requires a variant assumed de novo in a patient whose phenotype matches the gene's disease association; with no proband/family data the criterion is not assessable. Not assessed due to insufficient evidence.

Rule

PM6 (moderate, pathogenic): Assumed de novo, but without confirmation of maternity and paternity (ACMG/AMP 2015, PMID:25741868).

Evidence considered

• PM6 definition from ACMG/AMP 2015 (PMID:25741868): 'PM6 applies if identity is assumed but not confirmed' for de novo variants; used as the generic rule because the DDX41 VCEP ruleset content was not retrievable (cspec, vcep_materials.json framework_complete=false).
• No source in the bundle (case_summary.json, evidence.json, prefetch.json, literature_pass.json, clinvar) reports parental testing or an assumed de novo origin for c.1479C>T.
• ClinVar submissions (clinvar) are germline laboratory classifications without family-testing details and cannot supply de novo evidence.
• No variant-specific case report for c.1479C>T was found in the retrieved publications or literature_pass.json.

Still missing

• No parental testing results or de novo assumption reported in any bundle source.
• No proband phenotype information to evaluate consistency with DDX41-related hematologic malignancy predisposition.
• DDX41 VCEP (cspec) ruleset content not retrieved; VCEP-specific PM6 wording could not be checked.

Sources

Reasoning

PP1 requires co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. No segregation data exist for c.1479C>T: no affected relatives were tested, no meioses observed, and no variant-specific case reports or family studies were found in literature_pass.json or the retrieved full texts. The generic ACMG/AMP 2015 (PMID:25741868) definition applies because the DDX41 VCEP ruleset text was not retrievable (cspec framework_complete=false). Not assessed due to insufficient evidence.

Rule

PP1 (supporting, pathogenic): Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG/AMP 2015, PMID:25741868).

Evidence considered

• PP1 (supporting): co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG/AMP 2015, PMID:25741868); used as the generic rule because the DDX41 VCEP ruleset content was not retrievable (cspec, vcep_materials.json empty rule_payload).
• No segregation, pedigree, or affected-relative testing data appear in case_summary.json, evidence.json, prefetch.json, or literature_pass.json.
• literature_pass.json lists no case reports for this variant; the two high-priority papers (PMID:25730230 expanded carrier screening; PMID:25741868 ACMG/AMP standards) do not mention c.1479C>T and provide no segregation data.
• Full-text search of retrieved publications found no occurrence of c.1479C>T or p.Ser493.

Still missing

• No affected-family-member segregation data; number of informative meioses unknown.
• No variant-specific case reports or family studies identified in the literature pass or available full texts.
• DDX41 VCEP (cspec) ruleset content not retrieved; VCEP-specific PP1 wording could not be checked.

Sources

Reasoning

PP4 (phenotype specificity) requires proband phenotype or family-history data, and none are present in the case bundle: there is no proband section, clinical presentation, or pedigree anywhere in the consolidated evidence. ClinVar condition labels for the variant are non-specific ('DDX41-related disorder', 'Inborn genetic diseases', 'not provided', 'not specified'). The variant is synonymous (p.Ser493=) with SpliceAI max delta 0.015 (no predicted splice consequence), so no functional basis for a phenotype-specific effect is evident from available data. Evidence is insufficient; the criterion is not assessed and the gap is the missing proband phenotype.

Rule

ACMG/AMP 2015 PP4 (generic fallback; PMID:25741868 via generic_acmg_combination_rules): patient's phenotype or family history is highly specific for a disease with a single genetic etiology (supporting).

Evidence considered

• Searched the consolidated case-evidence bundle for proband phenotype, clinical history, and family history content; none is present, so PP4 cannot be evaluated.
• ClinVar VCV000726954 condition labels are non-specific: 'DDX41-related disorder', 'Inborn genetic diseases', 'not provided', 'not specified' — no specific phenotype is attached.
• Variant is synonymous (NP_057306.2:p.(Ser493=)) with SpliceAI max delta 0.015, indicating no predicted splice impact; no functional basis for a DDX41 phenotype-specific effect is evident from the bundle.
• Governing DDX41 CSPEC v1.0 specification (doc 1625925053) has an empty ruleset, so no gene-specific PP4 rule exists; the generic ACMG/AMP 2015 PP4 definition (phenotype or family history highly specific for a disease with a single genetic etiology) would govern if proband data were available.

Still missing

• No proband phenotype, clinical presentation, or family history is provided in the case bundle; a human reviewer with access to case records is required to evaluate DDX41-related hematologic malignancy phenotype specificity.

Sources

Reasoning

BS3 (well-established functional studies show no damaging effect; Richards et al. 2015, PMID:25741868) cannot be evaluated because no well-established functional study of NM_016222.2:c.1479C>T (p.(Ser493=)) is available. The variant is synonymous, so any functional impact would most plausibly be splicing-mediated, but no RNA/cDNA or minigene data exist in the case bundle. SpliceAI (max delta 0.015) indicates no predicted splicing impact, but in-silico splicing prediction is not a functional study and does not meet the BS3 evidentiary bar (it is BP7-type evidence outside this group's remit). Governing framework: the cspec DDX41 Myeloid Malignancy EP v1.0 specification has an empty rule payload (framework_complete=false), so generic ACMG/AMP 2015 definitions apply. ClinVar's Benign/Likely benign laboratory classifications were reviewed but are final classifications, not functional assay evidence, and were not used to infer BS3. With no functional assay data, BS3 must remain not assessed; absence of assay evidence must not be conflated with evidence of no damaging effect.

Rule

generic_acmg_2015_PS3_BS3 (PMID:25741868); no gene-specific rule extractable from cspec payload

Evidence considered

• Framework check: cspec DDX41 Myeloid Malignancy EP v1.0 (doc 1625925053) is present but rule_payload is empty (unstructured_ruleset, framework_complete=false); no gene-specific functional criteria could be applied, so generic ACMG/AMP 2015 (PMID:25741868) governs PS3/BS3.
• ACMG/AMP 2015 (PMID:25741868) defines BS3 as well-established functional studies showing no damaging effect; the guideline cautions that not all functional studies predict protein impact and that assay validity (biological relevance, validation, reproducibility) must be considered.
• Variant is synonymous (NP_057306.2:p.(Ser493=)); a damaging effect would most plausibly be splicing-mediated, making mRNA-level assays (RNA/cDNA, minigene) the relevant class of functional evidence, and none are present in the case bundle.
• SpliceAI max delta score 0.015 predicts no significant splice impact, but this is an in-silico prediction only; it does not constitute a well-established functional study and is insufficient for BS3 (in-silico splicing evidence is BP7-type and outside this group).
• OncoKB (queried DDX41/S493=) lists 'Unknown Oncogenic Effect' with is_variant_specific=false; provides no variant-specific functional data.
• COSMIC reports somatic occurrence only (COSV57251228, n=2); not functional assay evidence and not used for BS3.
• ClinVar (VCV000726954) submissions are laboratory classifications (Benign x3, Likely benign x1) with no attached functional assay data; per policy, final classifications from other sources were not used to infer BS3.
• Literature pass (literature_pass.json) returned 7 PMIDs, none describing functional studies of c.1479C>T; absence of assay evidence is not evidence of no damaging effect.

Still missing

• No variant-specific functional assay evidence (RNA/cDNA analysis, minigene splicing assay, protein-level or cellular assay) for c.1479C>T is available; well-established functional studies would be required to apply BS3, particularly mRNA-level assays given the synonymous consequence.

Sources

Reasoning

BS4 (strong, benign) requires documented lack of segregation in affected family members. The case bundle contains no family testing data whatsoever for c.1479C>T — no affected family members were tested, so absence of segregation can neither be confirmed nor refuted. ClinVar laboratory classifications (Benign/Likely benign) are not a substitute for segregation data and are not used to infer this criterion. Not assessed due to insufficient evidence.

Rule

BS4 (strong, benign): Lack of segregation in affected family members (ACMG/AMP 2015, PMID:25741868).

Evidence considered

• BS4 (strong, benign): lack of segregation in affected family members (ACMG/AMP 2015, PMID:25741868); used as the generic rule because the DDX41 VCEP ruleset content was not retrievable (cspec, vcep_materials.json framework_complete=false).
• No family/pedigree data are present in the case bundle (case_summary.json, evidence.json, prefetch.json, literature_pass.json), so lack of segregation cannot be documented.
• ClinVar (clinvar) 4 germline laboratory submissions (3 Benign, 1 Likely benign) contain no segregation or family-testing assertions; final classifications from other sources are never used to infer this criterion.
• No variant-specific case reports found in literature_pass.json or the retrieved publications.

Still missing

• No family testing data at all; cannot determine lack of segregation in affected family members.
• No variant-specific family studies in the literature pass or retrieved full texts.
• DDX41 VCEP (cspec) ruleset content not retrieved; VCEP-specific BS4 wording could not be checked.

Sources

Reasoning

BP2 (supporting benign) is an observational criterion requiring phase data: the variant observed in trans with a pathogenic variant in the context of a dominant disorder, or observed in cis with a pathogenic variant in any inheritance pattern. DDX41 syndrome is autosomal dominant (CSPEC), so the relevant clause is in-trans-with-a-pathogenic-variant in a dominant disorder. The evidence bundle contains no proband or family-level phase observations for this variant: ClinVar VCV000726954 (NM_016222.4(DDX41):c.1479C>T p.Ser493=) holds 4 germline clinical submissions (3 Benign, 1 Likely benign; review status 'criteria provided, multiple submitters, no conflicts') with no criterion-level or cis/trans information (usable_for_criterion_leads = 0, no validated PMIDs, no expert panel submissions), and none of the retrieved publications report this variant or any phase/segregation observation. Evidence is insufficient to apply BP2.

Rule

Generic ACMG/AMP 2015 (PMID 25741868) BP2: supporting evidence for a benign impact when a variant is observed in trans with a pathogenic variant in the context of dominant disorders, or in cis with a pathogenic variant in any inheritance pattern. CSPEC DDX41 v1.0 payload contains no BP2 specification, so the generic rule governs.

Evidence considered

• PMID:25741868 (ACMG/AMP 2015 standards): BP2 is supporting evidence for a benign impact 'in the context of dominant disorders, the detection of a variant in trans with a pathogenic variant', and 'finding the second variant in cis would be supporting evidence, though not definitive, for a benign role (BP2)'.
• cspec (ClinGen Myeloid Malignancy Expert Panel, DDX41 v1.0): establishes autosomal dominant inheritance for DDX41-related hematologic malignancy predisposition syndrome, which is the disease context required for BP2's in-trans-with-pathogenic variant clause; the payload contains no BP2 specification, so the generic rule governs.
• clinvar (VCV000726954): consulted for observational phase data - 4 germline submissions (3 Benign, 1 Likely benign), review status 'criteria provided, multiple submitters, no conflicts'; usable_for_criterion_leads = 0, no expert panel submissions, no validated PMIDs; no submission reports cis/trans phase or case/family observations, so no BP2 phase evidence can be drawn from this source.
• Literature packet review: none of the retrieved publications (e.g., PMID:25730230 carrier screening, newborn-screening background papers) mention this variant or any DDX41 phase observation relevant to BP2.

Still missing

• No case/family-level data documenting the variant in trans with a pathogenic DDX41 variant (dominant-disease clause) or in cis with a pathogenic variant.
• No parental testing, segregation, or phase-determination studies for this variant exist in the bundle; ClinVar submissions carry no phase information and no validated PMIDs.

Sources

Reasoning

BP5 (variant found in a case with an alternate molecular basis for disease) requires proband-level findings demonstrating an alternative cause of the phenotype. The case bundle contains no proband data whatsoever — no alternate molecular basis, no co-occurring variant, no diagnostic workup information. Evidence is insufficient; the criterion is not assessed and the gap is the missing proband context.

Rule

ACMG/AMP 2015 BP5 (generic fallback; PMID:25741868 via generic_acmg_combination_rules): variant found in a case with an alternate molecular basis for disease (supporting).

Evidence considered

• Searched the consolidated case-evidence bundle for any proband-level findings (co-occurring variants, alternative diagnoses, alternate molecular basis); none is present.
• Generic ACMG/AMP 2015 BP5 rule (variant found in a case with an alternate molecular basis for disease) governs because the DDX41 CSPEC v1.0 ruleset is empty; without proband data the criterion cannot be evaluated.

Still missing

• No proband-level data are available to determine whether an alternate molecular basis for the disease is present in the case; a human reviewer with case records is required to resolve BP5.

Sources