Variant classification summary

NM_001042492.2:c.8161-1_8161delinsCT

NF1 · NP_001035957.1:p.? · NM_001042492.2

GRCh37: chr17:29687504 GC>CT · GRCh38: chr17:31360486 GC>CT

Gene: NF1 Transcript: NM_001042492.2

Final call

VUS

PVS1 moderate PM2 supporting PP3 moderate

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 moderate: predicted NMD escape with less than 10% coding-sequence loss supports the ClinGen SVI downgrade.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

3

PP3 moderate: SpliceAI maximum delta 0.996 exceeds the generic splice-impact threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, two moderate criteria plus one supporting criterion do not meet a Likely Pathogenic or Pathogenic combination, resulting in VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met, moderate: SVI downgrades canonical splice variants with predicted NMD escape and <10% coding-sequence loss; exon 56 is 217 of 8,520 coding nucleotides.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001042492.2:c.8161-1_8161delinsCT in NF1 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001035957.1:p.?. As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband de novo result, parental genotypes, or maternity/paternity confirmation is documented.	cspec
PS3	Not assessed	Not assessed: no validated functional assay is reported for the variant; SpliceAI max delta 0.996 is computational, not experimental evidence.	cspec spliceai
PS4	Not assessed	Not assessed: no variant-specific case-control counts, odds ratio, or other disease-enrichment result was available.
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001042492.2:c.8161-1_8161delinsCT in NF1 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001035957.1:p.?. As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with AF 0 below the <=0.0001 PM2 threshold.	cspec gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	N/A	Not applicable: NF1 is autosomal dominant, so biallelic-in-trans evidence is not the relevant inheritance model.	cspec generic_acmg_combination_rules
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001042492.2:c.8161-1_8161delinsCT in NF1 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001035957.1:p.?. As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001042492.2:c.8161-1_8161delinsCT in NF1 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001035957.1:p.?. As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no credible untested-parent de novo observation or proband phenotype is documented.	cspec
PP1	Not assessed	Not assessed: no affected relatives, unaffected relatives, informative meioses, or segregation results are documented.	cspec
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001042492.2:c.8161-1_8161delinsCT in NF1 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001035957.1:p.?. As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	Met	Met at moderate strength: SpliceAI maximum delta 0.996 exceeds the >=0.5 PP3 threshold.	cspec spliceai
PP4	Not assessed	Not assessed: no patient phenotype, diagnostic features, or family-history information was available to establish NF1 specificity.
PP5	Not met	Not met: ClinVar had no exact-variant record, so no Expert Panel Pathogenic or Likely pathogenic classification supports PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, providing no allele frequency near the >=0.05 BA1 threshold.	cspec gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, so no frequency approaches the >=0.01 BS1 threshold.	cspec gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not assessed	Not assessed: population databases report absence, with no healthy-carrier observation or NF1 penetrance data to evaluate the BS2 premise.	cspec gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no validated benign functional assay is reported; the available SpliceAI max delta is 0.996 and predicts splice impact.	cspec spliceai
BS4	Not assessed	Not assessed: no affected relatives lacking the variant or informative non-segregation results are documented.	cspec
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001042492.2:c.8161-1_8161delinsCT in NF1 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001035957.1:p.?. As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no affected-proband or phase data show this variant in trans with a pathogenic NF1 variant.	cspec generic_acmg_combination_rules
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001042492.2:c.8161-1_8161delinsCT in NF1 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001035957.1:p.?. As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI maximum delta 0.996 exceeds the <=0.1 BP4 threshold.	cspec spliceai
BP5	Not assessed	Not assessed: no alternate pathogenic variant or molecular diagnosis was documented to explain the phenotype.
BP6	Not met	Not met: ClinVar had no exact-variant record, so no Expert Panel Benign or Likely benign classification supports BP6.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001042492.2:c.8161-1_8161delinsCT in NF1 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001035957.1:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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