Variant classification summary

NM_001042492.2:c.4375_4377del

NF1 · NP_001035957.1:p.(Glu1459del) · NM_001042492.2

GRCh37: chr17:29586086 AAAG>A · GRCh38: chr17:31259068 AAAG>A

Gene: NF1 Transcript: NM_001042492.2

Final call

VUS

PM2 supporting PM4 moderate

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.(Glu1459del)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

PM4 moderate: the 3-bp in-frame deletion produces p.(Glu1459del), a one-amino-acid protein-length change.

Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate criterion plus one supporting criterion does 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	N/A	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001042492.2:c.4375_4377del in NF1 is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_001035957.1:p.(Glu1459del). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1'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
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.4375_4377del in NF1 is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_001035957.1:p.(Glu1459del). 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: ClinVar reports one de novo case with confirmed parentage, but the candidate record is not an exact match and parental genotypes are unavailable.	clinvar
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or measured effect was reported for p.(Glu1459del).	cspec PMID:12807981 PMID:15060124 PMID:26962827 PMID:31776437 clinvar
PS4	Not met	Not met: no case-control enrichment, odds ratio, likelihood ratio, or statistically significant phenotype prevalence was reported for exact variant c.4375_4377del.	PMID:12807981 PMID:15060124 PMID:26962827 PMID:31776437 clinvar cspec
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.4375_4377del in NF1 is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_001035957.1:p.(Glu1459del). 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 strength: the variant is absent from gnomAD v2.1 and v4.1, giving frequency 0 versus the PM2 threshold of <=0.0001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: NF1 is autosomal dominant, so PM3's affected-proband evidence for pathogenic variants on both alleles does not apply.	cspec generic_acmg_combination_rules
PM4	Met	Met: NM_001042492.2:c.4375_4377del is a 3-bp in-frame deletion producing p.(Glu1459del), a one-amino-acid protein-length change meeting generic PM4.	cspec 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.4375_4377del in NF1 is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_001035957.1:p.(Glu1459del). 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: an apparently de novo claim lacks verifiable exact-variant documentation and the parental-testing details required for PM6.	clinvar
PP1	Not assessed	Not assessed: no variant-positive affected relatives or informative cosegregating meioses are documented for this exact NF1 deletion.	PMID:26962827 PMID:12807981
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.4375_4377del in NF1 is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_001035957.1:p.(Glu1459del). 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	N/A	Not applicable: this exonic in-frame deletion produces p.(Glu1459del), outside PP3's missense and intronic/splice-region scope.	cspec
PP4	Not assessed	Not assessed: no patient-specific, highly specific NF1 phenotype was documented to support PP4 for this exact variant.	clinvar PMID:26962827 PMID:31776437 cspec
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic assertion; available entries are non-expert submissions or aggregate labels.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the BA1 threshold of >=0.05.	cspec gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: the variant is absent from gnomAD, with observed frequency 0 versus the generic BS1 threshold of >=0.01.	cspec gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not assessed	Not assessed: gnomAD absence provides no qualifying observation of the variant in healthy individuals or homozygotes for BS2.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated assay demonstrated normal NF1 function for p.(Glu1459del).	cspec PMID:12807981 PMID:15060124 PMID:26962827 PMID:31776437
BS4	Not assessed	Not assessed: no unaffected variant carriers or other informative non-segregation observations are documented for this exact deletion.	PMID:26962827 PMID:12807981
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.4375_4377del in NF1 is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_001035957.1:p.(Glu1459del). 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 data or cis/trans phase result with another pathogenic NF1 variant is available for this deletion.	cspec generic_acmg_combination_rules
BP3	Not met	Not met: the one-amino-acid in-frame deletion is described as occurring in a non-repeat region, so BP3's repeat-region requirement is not satisfied.	clinvar cspec generic_acmg_combination_rules
BP4	N/A	Not applicable: this exonic in-frame deletion produces p.(Glu1459del), outside BP4's missense and intronic/splice-region scope.	cspec
BP5	Not assessed	Not assessed: no case-specific alternative molecular etiology was documented, and no NF1-specific BP5 threshold was available for comparison.	cspec clinvar
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely benign classification was found; available submissions are non-expert pathogenic or likely pathogenic assertions.	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.4375_4377del in NF1 is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_001035957.1:p.(Glu1459del). 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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