Variant classification summary

NM_001042492.2:c.1806A>G

NF1 · NP_001035957.1:p.(Glu602=) · NM_001042492.2

GRCh37: chr17:29550546 A>G · GRCh38: chr17:31223528 A>G

Gene: NF1 Transcript: NM_001042492.2

Final call

VUS

BP7 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.(Glu602=)

gnomAD AF

3.596247997261891e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP7 supporting is met because synonymous p.Glu602= has SpliceAI maximum delta 0.078, below the 0.1 cutoff.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting benign criterion alone does not meet a benign or likely benign threshold, so the variant remains a 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.1806A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Glu602=). 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.1806A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Glu602=). 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 documented parental genotypes or confirmed de novo occurrence are available for NM_001042492.2:c.1806A>G.	cspec PMID:23460398 PMID:29872168
PS3	Not assessed	Not assessed: no validated RNA, protein, or cellular assay directly evaluates NF1 c.1806A>G (p.Glu602=).	cspec PMID:10678181 PMID:23460398 PMID:29872168 spliceai
PS4	Not assessed	Not assessed: no exact-variant case-control enrichment, affected-case series, or odds ratio is available for NM_001042492.2:c.1806A>G.	cspec PMID:10678181 PMID:23460398 PMID:29872168
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.1806A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Glu602=). 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	Not met	Not met: the highest ancestry-specific allele frequency is 1.01764e-04, exceeding the generic PM2 cutoff of 0.0001.	cspec gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: NF1 is autosomal dominant, whereas PM3 requires affected individuals with biallelic variants in a recessive disorder.	cspec
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.1806A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Glu602=). 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.1806A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Glu602=). 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 affected individual with this exact variant is documented as apparently de novo without parental testing.	cspec PMID:23460398 PMID:29872168
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or family segregation data are reported for this exact variant.	cspec PMID:23460398 PMID:29872168
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.1806A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Glu602=). 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: the variant is synonymous (p.Glu602=), outside the specified PP3 scope for missense or intronic/splice-region variants.	cspec
PP4	Not assessed	Not assessed: no proband phenotype or highly specific NF1 clinical presentation is documented for this variant.	cspec
PP5	Not met	Not met: ClinVar shows 0 expert-panel submissions, and the exact-variant record contains no expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 1.01764e-04, far below the generic BA1 threshold of 0.05.	cspec gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest observed allele frequency is 1.01764e-04, below the generic BS1 threshold of 0.01.	cspec gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD shows carriers but provides no documented unaffected adult status or phenotype assessment to satisfy BS2.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated assay demonstrates normal NF1 function for c.1806A>G (p.Glu602=).	cspec PMID:26467025 PMID:23460398 PMID:29872168 spliceai
BS4	Not assessed	Not assessed: no confirmed variant-positive unaffected relatives with reliable age-appropriate phenotyping 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.1806A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Glu602=). 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 co-occurrence or cis/trans phase data with a pathogenic variant are documented for c.1806A>G.
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.1806A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Glu602=). 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	N/A	Not applicable: the variant is synonymous (p.Glu602=), outside the specified BP4 scope for missense or intronic/splice-region variants.	cspec
BP5	Not assessed	Not assessed: no affected individual with this variant and a separate pathogenic explanation, or BP5-specific likelihood ratio, is documented.	cspec clinvar
BP6	Not met	Not met: ClinVar shows 0 expert-panel submissions, so non-expert Benign and Likely benign assertions cannot trigger BP6.	clinvar
BP7	Met	Met, supporting: synonymous p.Glu602= with SpliceAI maximum delta 0.078 below the <=0.1 no-significant-splice-impact cutoff.	spliceai cspec

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