NF1 c.4577+11C>G, p.?

Reasoning

gnomAD v4.1 reports 6 homozygotes for this allele, including homozygotes in the overall population, and the non-cancer datasets report 1 homozygote in gnomAD v3.1 non-cancer. NF1 is an autosomal-dominant disorder with substantial penetrance, so recurrent homozygosity in an ostensibly population-based cohort is strong benign evidence under BS2. Because gnomAD participants are not individually phenotype-verified for NF1 and the NF1 specification does not provide a specific BS2 rule payload, human review is retained.

Evidence considered

• The NF1 ClinGen specification identifies autosomal-dominant NF1 but provides no usable BS2-specific rule payload in the retrieved framework.
• gnomAD v4.1 reports total homozygote count 6 for the variant.
• The retrieved non-cancer population records report one homozygote in gnomAD v3.1 non-cancer and zero in gnomAD v2.1 non-cancer exomes.
• Multiple homozygotes in population data are inconsistent with a highly penetrant autosomal-dominant NF1 pathogenic allele, although individual participant phenotypes are not available.

Still missing

• Individual NF1 phenotypes and ascertainment status are unavailable for the gnomAD homozygotes.

Sources

Reasoning

The variant is intronic (NM_001042492.2:c.4577+11C>G), so BP4 is evaluated through the SpliceAI path only. The governing NF1 VCEP framework is present but contains no criterion-specific BP4 rule; therefore the supplied generic SpliceAI calibration applies. SpliceAI is available and the maximum delta score is 0.005, which is at or below the BP4 supporting threshold of 0.1 (Jaganathan et al. 2019, PMID:30661751). Thus BP4 is met at supporting strength.

Rule

Intronic/splice-region variant: SpliceAI max delta <=0.1 supports BP4; maximum delta 0.005 meets this threshold.

Evidence considered

• The variant is intronic, so BP4 was assessed using SpliceAI only; REVEL is not applicable.
• SpliceAI reports a maximum delta score of 0.005 (DS_AG 0.005, DS_AL 0.001, DS_DG 0.0, DS_DL 0.0).
• The NF1 VCEP framework is present but provides no criterion-specific BP4 threshold, so the supplied generic calibration was used: BP4 supporting <=0.1, from Jaganathan et al. 2019 (PMID:30661751).

Sources

Reasoning

PVS1 is not met. NM_001042492.2:c.4577+11C>G is an intronic, non-canonical splice-position variant rather than a nonsense, frameshift, or canonical ±1,2 splice variant. The generic ClinGen SVI PVS1 framework therefore does not provide a default null-variant assignment, and there is no transcript- or protein-level evidence demonstrating loss of function. SpliceAI predicts a maximum delta of 0.005, below the generic supporting splice-impact threshold of 0.2 and within the low-impact range; this does not establish aberrant splicing or NMD. No PVS1 downgrade tier is applicable because the criterion is not initiated for this non-null variant class.

Rule

Generic ClinGen SVI PVS1 framework: default PVS1 applies to established null-variant classes; this non-canonical intronic variant does not enter a PVS1 strength tier without demonstrated loss of function.

Evidence considered

• The NF1 CSPEC record is present but contains no criterion-specific rule payload for PVS1; the generic ClinGen SVI PVS1 framework is therefore used.
• The variant is NM_001042492.2:c.4577+11C>G, an intronic non-canonical splice-position change; the case assessment does not classify it as nonsense, frameshift, or canonical ±1,2 splice consensus.
• SpliceAI reports DS_AG 0.005, DS_AL 0.001, DS_DG 0.0, and DS_DL 0.0, with maximum delta 0.005; the generic splice-impact supporting threshold is >0.2.
• ACMG/AMP guidance states that splice-site effects can involve exon skipping, shortening, intronic inclusion, or alternative splice-site use and that predicted effects require RNA or protein confirmation; no such assay is available for this variant.

Still missing

• No RNA or minigene assay directly establishes whether c.4577+11C>G alters NF1 splicing.
• The affected exon and any resulting transcript or protein consequence are not established.

Sources

Reasoning

The NF1 ClinGen specification is present but contains no usable PM2 frequency rule, so the supplied generic PM2 supporting threshold of allele frequency <=0.0001 applies. The variant is present at AF 0.00097426 in gnomAD v4.1, 0.00108341 in gnomAD v2.1, 0.00109505 in gnomAD v2.1 non-cancer exomes, and 0.00123111 in gnomAD v3.1 non-cancer genomes; it is therefore not rare enough for PM2. Homozygotes are also observed.

Evidence considered

• The NF1 ClinGen specification contains no usable PM2 rule payload, so the supplied generic SVI PM2 threshold applies.
• gnomAD v4.1 reports AF 0.00097426 (1572/1613532 alleles; 6 homozygotes).
• gnomAD v2.1 reports AF 0.00108341 (306/282442 alleles; no homozygotes).
• The non-cancer subset records report gnomAD v2.1 non-cancer exomes AF 0.00109505 (259/236518 alleles; no homozygotes) and gnomAD v3.1 non-cancer genomes AF 0.00123111 (182/147834 alleles; 1 homozygote).
• The supplied generic PM2 calibration is allele frequency <=0.0001 (ClinGen SVI recommendation, PMID:25741868).

Sources

Reasoning

The variant is intronic (NM_001042492.2:c.4577+11C>G), so PP3 is evaluated through the SpliceAI path only. The governing NF1 VCEP framework is present but contains no criterion-specific PP3 rule; therefore the supplied generic SpliceAI calibration applies. SpliceAI is available and the maximum delta score is 0.005, below the PP3 supporting threshold of 0.2 and the moderate threshold of 0.5 (Jaganathan et al. 2019, PMID:30661751). Thus PP3 is not met.

Rule

Intronic/splice-region variant: SpliceAI max delta >=0.2 for PP3 supporting or >=0.5 for PP3 moderate; maximum delta 0.005 does not meet either threshold.

Evidence considered

• The variant is intronic, so PP3 was assessed using SpliceAI only; REVEL is not applicable.
• SpliceAI reports a maximum delta score of 0.005 (DS_AG 0.005, DS_AL 0.001, DS_DG 0.0, DS_DL 0.0).
• The NF1 VCEP framework is present but provides no criterion-specific PP3 threshold, so the supplied generic calibration was used: PP3 supporting >=0.2 and moderate >=0.5, from Jaganathan et al. 2019 (PMID:30661751).

Sources

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar variation 227741 is an exact match, but the submission audit reports zero expert-panel submissions; its available classifications are laboratory submissions, predominantly Likely benign or Benign, with single-submitter review status. Therefore PP5 is not met. The exact-variant ClinVar record cannot be used for PP5 merely because it has a classification or cited publications.

Rule

PP5: apply only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; ordinary submissions and aggregate labels are excluded.

Evidence considered

• ClinVar variation 227741 exactly matches NM_001042492.3(NF1):c.4577+11C>G, but the audit reports expert_panel_submissions = 0.
• The available ClinVar classifications are Likely benign and Benign with criteria provided, single submitter status; ordinary laboratory submissions and aggregate labels do not trigger PP5 under the specified rule.

Sources

Reasoning

The NF1 ClinGen specification is present but contains no usable population-frequency rule payload, so the supplied generic ACMG/AMP BA1 threshold of allele frequency >=0.05 applies. The highest broad-population frequency is 0.00792341 in gnomAD v4.1 Middle Eastern individuals, with grpmax FAF 0.00614044; the gnomAD v3.1 non-cancer maximum of 0.0769231 represents only 4 of 52 HGDP:MOZABITE alleles and is a small-ancestry-sample threshold artifact rather than a robust population estimate. Therefore BA1 is not met.

Evidence considered

• The NF1 ClinGen specification is the governing framework, but it provides no usable population-frequency threshold in the retrieved rule payload.
• gnomAD v4.1 reports AF 0.00097426 overall, highest population AF 0.00792341 in Middle Eastern individuals, and grpmax FAF 0.00614044.
• The gnomAD v3.1 non-cancer report includes a 0.0769231 frequency from only 4 of 52 HGDP:MOZABITE alleles; this sparse ancestry estimate is not treated as evidence for BA1.
• The supplied generic ACMG/AMP BA1 calibration is allele frequency >=0.05 (ACMG/AMP 2015, PMID:25741868).

Sources

Reasoning

The NF1 ClinGen specification is present but contains no usable BS1 frequency rule, so the supplied generic BS1 threshold of allele frequency >=0.01 applies. The maximum robust population estimate is gnomAD v4.1 Middle Eastern AF 0.00792341, while the overall AF is 0.00097426 and grpmax FAF is 0.00614044; the gnomAD v3.1 non-cancer 0.0769231 value is based on only 4 of 52 HGDP:MOZABITE alleles and is not reliable for threshold application. BS1 is therefore not met.

Evidence considered

• The NF1 ClinGen specification contains no usable BS1 rule payload, so the supplied generic SVI BS1 threshold applies.
• gnomAD v4.1 reports overall AF 0.00097426, Middle Eastern AF 0.00792341, and grpmax FAF 0.00614044.
• The gnomAD v3.1 non-cancer HGDP:MOZABITE estimate of 0.0769231 is based on 4 of 52 alleles and is treated as a sparse-ancestry threshold artifact.
• The supplied generic BS1 calibration is allele frequency >=0.01, with per-gene derivation preferred (Whiffin et al., PMID:28518168).

Sources

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar variation 227741 is an exact match, but the submission audit reports zero expert-panel submissions. Its Benign and Likely benign assertions are ordinary single-submitter laboratory submissions, so they must not trigger BP6 under the specified rule.

Rule

BP6: apply only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; ordinary submissions and aggregate labels are excluded.

Evidence considered

• ClinVar variation 227741 exactly matches NM_001042492.3(NF1):c.4577+11C>G, but the audit reports expert_panel_submissions = 0.
• The record contains Benign and Likely benign single-submitter laboratory assertions; these are explicitly excluded from BP6 under the specified rule.

Sources

Reasoning

The NF1 CSPEC framework is present but contains no usable criterion-specific rules. The reviewed case evidence documents the variant and general literature triage, but does not document a confirmed de novo occurrence in a proband, verified maternity and paternity, or parental testing demonstrating absence of NM_001042492.2:c.4577+11C>G. PMID:23460398 concerns other NF1 intronic variants in de novo adult AML and explicitly does not mention this variant; it therefore cannot establish PS2 for this case.

Evidence considered

• The NF1 CSPEC record is applicable but unstructured and contains no criterion-specific PS2 rule payload.
• The case materials provide no proband-parent segregation table, parental genotypes, maternity or paternity confirmation, or explicit confirmed de novo statement for NM_001042492.2:c.4577+11C>G.
• PMID:23460398 studied other NF1 intronic variants in 20 patients with de novo adult acute myeloid leukemia and does not mention c.4577+11C>G; it cannot support PS2 for this variant.

Still missing

• Documented proband genotype and confirmed maternity and paternity are unavailable.
• Parental testing results demonstrating absence or presence of the variant are unavailable.
• A phenotype-consistent, confirmed de novo case report for this exact variant is unavailable.

Sources

Reasoning

The NF1 VCEP specification is present but provides no usable criterion-specific functional rule in the available ruleset. The case evidence contains no variant-specific validated functional assay, RNA analysis, protein study, or other experimental result establishing that NM_001042492.2:c.4577+11C>G disrupts NF1 function or splicing. SpliceAI predicts a low maximum delta score of 0.005, but this is an in-silico prediction and cannot substitute for PS3 functional evidence. Therefore PS3 cannot be applied at any strength.

Evidence considered

• The NF1 VCEP/ClinGen specification was identified, but its retrieved ruleset contains no criterion-specific PS3 or BS3 rules.
• No case-specific RNA, protein, minigene, biochemical, cellular, or other validated functional assay result was found for NM_001042492.2:c.4577+11C>G.
• SpliceAI reports a maximum delta score of 0.005; this computational prediction is not experimental functional evidence.
• ACMG/AMP guidance states that predicted splice effects require confirmation by RNA or protein functional analysis; the cited paper does not report an assay for this variant.

Still missing

• A validated variant-specific functional study is needed, such as RNA/cDNA analysis or a validated minigene assay with appropriate positive and negative controls, to demonstrate abnormal NF1 splicing or function.
• No NF1 VCEP-specific PS3 strength calibration was available in the retrieved ruleset.

Sources

Reasoning

The NF1 VCEP/ClinGen framework was identified but contains no usable criterion-specific PS4 rule text. Generic PS4 requires significantly increased prevalence of the variant in affected individuals compared with controls, ordinarily supported by case-control enrichment or a well-established phenotype-specific series. The available evidence contains no case-control counts, odds ratio, relative risk, likelihood ratio, or reliable exact-variant affected-patient series. PMID:23460398 reports other NF1 intronic variants in adult acute myeloid leukemia and does not mention NM_001042492.2:c.4577+11C>G; therefore it cannot establish PS4 for this variant.

Rule

Generic PS4: significantly increased prevalence of the variant in affected individuals compared with controls; no applicable NF1-specific operator or threshold was available.

Evidence considered

• The retrieved NF1 Expert Panel framework identifies NF1 Version 1.0 but supplies no PS4 rule payload or criterion-specific threshold.
• The reviewed AML study reports other NF1 intronic variants and does not report the exact variant NM_001042492.2:c.4577+11C>G, affected/control enrichment, or an odds ratio for this variant.

Still missing

• Exact-variant clinical case series or case-control data with affected and control counts are unavailable.
• No criterion-specific NF1 VCEP PS4 rule text was available in the retrieved framework payload.

Sources

Reasoning

The NF1 ClinGen specification is the governing framework, but its retrieved rule payload contains no criterion-specific PM3 instructions. NF1 is documented as autosomal dominant, and the available case evidence does not identify an affected proband carrying this variant together with a known pathogenic NF1 variant, nor does it establish phase as confirmed in trans. No PM3 evidence can therefore be adjudicated from the supplied record. The decisive gap is the absence of a documented affected-proband observation with a pathogenic allele and validated trans phase.

Evidence considered

• The governing NF1 specification identifies autosomal dominant inheritance but provides no criterion-specific PM3 rule payload in the retrieved framework.
• The case record contains no documented affected proband, second pathogenic NF1 variant, or confirmed trans phase for this variant.

Still missing

• Affected-proband data showing this variant with a known pathogenic NF1 variant
• Confirmed phase demonstrating the variants are in trans
• Evidence that the comparator NF1 variant is pathogenic

Sources

Reasoning

The NF1 CSPEC framework is present but contains no usable criterion-specific rules. No case report or clinical record reviewed here documents NM_001042492.2:c.4577+11C>G as apparently de novo without parental confirmation. PMID:23460398 reports different NF1 intronic variants in de novo adult AML, not this variant, and cannot establish PM6.

Evidence considered

• The NF1 CSPEC record is applicable but unstructured and contains no criterion-specific PM6 rule payload.
• The reviewed evidence contains no exact-variant case with an apparently de novo result and no parental testing.
• PMID:23460398 concerns other NF1 intronic variants and does not mention c.4577+11C>G; its use of de novo in the disease context is not evidence for PM6 for this variant.

Still missing

• An exact-variant report with an apparently de novo occurrence is unavailable.
• The parental testing status for any reported proband is unavailable.
• Phenotype-consistent clinical details for an exact-variant de novo case are unavailable.

Sources

Reasoning

The NF1 CSPEC framework is present but contains no usable criterion-specific rules. The reviewed case evidence does not identify affected relatives carrying NM_001042492.2:c.4577+11C>G, provide informative meioses, or report phenotype-consistent familial segregation. Therefore PP1 cannot be assigned at any strength.

Evidence considered

• The NF1 CSPEC record is applicable but unstructured and contains no criterion-specific PP1 rule payload.
• The reviewed case materials provide no pedigree, affected-relative genotypes, informative meioses, or exact-variant segregation data.
• No publication in the reviewed exact-variant literature set reports familial segregation of NM_001042492.2:c.4577+11C>G.

Still missing

• A pedigree or family history with informative affected relatives is unavailable.
• Genotypes of relatives and the number of informative meioses are unavailable.
• Phenotype concordance among variant-positive relatives is unavailable.

Sources

Reasoning

The available case materials do not provide a patient phenotype, a disease-specific clinical presentation, or an exact-variant phenotype correlation. The NF1 VCEP framework payload contains no PP4 rule text. General NF1 background statements and papers not reporting this exact variant cannot establish that the patient's phenotype is highly specific for NF1 caused by this variant.

Rule

Generic PP4: patient phenotype or family history is highly specific for a disease with a single-gene etiology; no applicable NF1-specific rule text was available.

Evidence considered

• The available case record identifies the variant and gene but supplies no patient phenotype or disease-specific clinical findings.
• The retrieved NF1 Expert Panel framework supplies no PP4 rule payload or phenotype-specific threshold.

Still missing

• Patient-level phenotype and diagnostic criteria are not available.
• No criterion-specific NF1 VCEP PP4 rule text was available in the retrieved framework payload.

Sources

Reasoning

The NF1 VCEP specification is present but provides no usable criterion-specific benign-functional rule in the available ruleset. The case evidence contains no variant-specific validated functional assay, RNA analysis, protein study, or other experimental result demonstrating normal NF1 function or normal splicing for NM_001042492.2:c.4577+11C>G. The low SpliceAI maximum delta score of 0.005 is computational evidence only and does not establish BS3. Therefore BS3 cannot be applied at any strength.

Evidence considered

• The NF1 VCEP/ClinGen specification was identified, but its retrieved ruleset contains no criterion-specific PS3 or BS3 rules.
• No case-specific RNA, protein, minigene, biochemical, cellular, or other validated functional assay result was found for NM_001042492.2:c.4577+11C>G.
• SpliceAI reports a maximum delta score of 0.005; this computational prediction is not validated benign functional evidence and cannot establish BS3.
• ACMG/AMP guidance indicates that splice effects require functional confirmation by RNA or protein analysis; the cited paper does not report a normal-function assay for this variant.

Still missing

• A validated variant-specific benign functional study is needed, such as RNA/cDNA analysis or a validated minigene assay with appropriate controls, showing normal NF1 splicing or function.
• No NF1 VCEP-specific BS3 strength calibration was available in the retrieved ruleset.

Sources

Reasoning

The NF1 CSPEC framework is present but contains no usable criterion-specific rules. The reviewed case evidence does not document an unaffected relative who was tested and carried NM_001042492.2:c.4577+11C>G, nor does it provide age, phenotype, penetrance, or ascertainment information needed to interpret non-segregation. BS4 is therefore not assessed.

Evidence considered

• The NF1 CSPEC record is applicable but unstructured and contains no criterion-specific BS4 rule payload.
• The reviewed case materials contain no non-segregation analysis involving tested unaffected relatives.
• No evidence establishes that any variant-positive unaffected relative was sufficiently aged and clinically evaluated for BS4 interpretation.

Still missing

• Tested unaffected relatives carrying the variant are not documented.
• Relative ages, clinical evaluations, and phenotype ascertainment are unavailable.
• Family structure and penetrance-relevant follow-up are unavailable.

Sources

Reasoning

The NF1 ClinGen specification is the governing framework, but its retrieved rule payload contains no criterion-specific BP2 instructions. NF1 is documented as autosomal dominant, for which BP2 requires appropriate allelic evidence such as this variant observed in trans with a pathogenic NF1 variant in a relevant individual or family context. The available case evidence contains no such phase-resolved observation and does not establish an unaffected or otherwise informative individual context. BP2 therefore cannot be adjudicated. The decisive gap is missing phase-resolved allelic and phenotype information.

Evidence considered

• The governing NF1 specification identifies autosomal dominant inheritance but provides no criterion-specific BP2 rule payload in the retrieved framework.
• The case record contains no phase-resolved allelic observation or informative clinical/family context supporting BP2.

Still missing

• Phase-resolved observation with a known pathogenic NF1 variant
• Informative clinical or family context supporting BP2 application
• Evidence that the comparator NF1 variant is pathogenic

Sources

Reasoning

No evidence shows that this exact variant was identified in an affected individual with a confirmed alternative molecular explanation for the phenotype. The available ClinVar submissions are not a substitute for BP5-level clinical evidence, and the reviewed literature does not report this exact variant in a phenotype-defined case with an alternative molecular diagnosis. No BP5-specific NF1 VCEP rule text or numeric likelihood-ratio threshold was available, so no numeric comparison can be performed.

Rule

Generic BP5: variant found in an affected individual with an alternative molecular basis for disease; no applicable NF1-specific rule text or threshold was available.

Evidence considered

• The available evidence does not document the exact variant in an affected individual whose phenotype is explained by another molecular diagnosis.
• ClinVar laboratory classifications are not sufficient by themselves to establish BP5, and no applicable NF1-specific BP5 threshold was retrieved.

Still missing

• Affected-individual evidence with a confirmed alternative molecular diagnosis is unavailable.
• No criterion-specific NF1 VCEP BP5 rule text or threshold was available in the retrieved framework payload.

Sources