Variant classification summary

NM_001042492.2:c.7584A>G

NF1 · NP_001035957.1:p.(Gln2528=) · NM_001042492.2

GRCh37: chr17:29679401 A>G · GRCh38: chr17:31352383 A>G

Gene: NF1 Transcript: NM_001042492.2

Final call

Likely Benign

BS2 strong BP4 supporting BP7 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.(Gln2528=)

gnomAD AF

0.0009776745719111246 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS2 strong: gnomAD v4.1 reports six homozygotes, inconsistent with a highly penetrant autosomal-dominant NF1 allele.

2

BP4 supporting: SpliceAI maximum delta 0.001 predicts no splice impact.

3

BP7 supporting: the synonymous variant is outside the canonical splice consensus with minimal predicted splice impact.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong benign criterion plus at least one supporting benign criterion leads to Likely Benign.

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.7584A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Gln2528=). 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.7584A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Gln2528=). 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 confirmed parental genotypes or maternity/paternity evidence establish that c.7584A>G arose de novo in the proband.	cspec PMID:25741868
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or transcript result was reported for c.7584A>G (p.Gln2528=).	cspec PMID:25741868
PS4	Not met	Not met: reviewed studies provide no exact-variant affected-case series or case-control enrichment for NF1 c.7584A>G.	cspec PMID:10678181 PMID:23460398 clinvar
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.7584A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Gln2528=). 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: gnomAD v4.1 overall AF is 0.000977675, above the 0.0001 supporting PM2 threshold.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: NF1 is specified as autosomal dominant, so recessive biallelic evidence for PM3 is not relevant to this condition.	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.7584A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Gln2528=). 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.7584A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Gln2528=). 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 documented family testing supports even a presumed de novo origin of c.7584A>G.	cspec PMID:25741868
PP1	Not assessed	Not assessed: zero informative affected-relative genotypes or meioses are documented for segregation of c.7584A>G.	cspec PMID:25741868
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.7584A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Gln2528=). 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	Not met	Not met: synonymous variant uses SpliceAI, whose maximum delta score is 0.001, below the 0.2 PP3 supporting threshold.	cspec spliceai
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific diagnostic features are documented for evaluating phenotype specificity.
PP5	Not met	Not met: ClinVar reports zero expert-panel submissions for the exact variant, and available laboratory labels are not eligible for PP5.	clinvar cspec
BA1	Not met	Not met: maximum observed all-comers population AF is 0.00909, below the 0.05 stand-alone threshold.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: maximum observed all-comers population AF is 0.00909, below the 0.01 strong threshold.	cspec gnomad_v4 gnomad_v2
BS2	Met	Met: gnomAD v4.1 contains 6 homozygotes, incompatible with a highly penetrant autosomal-dominant NF1 allele.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no variant-specific validated assay demonstrated normal function or normal transcript processing for c.7584A>G (p.Gln2528=).	cspec PMID:25741868
BS4	Not assessed	Not assessed: no informative unaffected relatives carrying c.7584A>G are documented for non-segregation.	cspec PMID:25741868
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.7584A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Gln2528=). 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 observation with a second pathogenic variant and no reliable cis/trans phase information are documented.	cspec
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.7584A>G in NF1 is a synonymous (silent) substitution predicted to produce NP_001035957.1:p.(Gln2528=). 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	Met	Met, supporting: synonymous variant has a SpliceAI maximum delta score of 0.001, meeting the <=0.1 BP4 threshold.	cspec spliceai
BP5	Not assessed	Not assessed: no patient-level alternative molecular diagnosis is documented to explain the phenotype independently of this NF1 variant.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel classification, so laboratory Benign or Likely benign labels cannot trigger BP6.	clinvar cspec
BP7	Met	Met, supporting: synonymous c.7584A>G is non-canonical and has a minimal SpliceAI maximum delta score of 0.001.	cspec spliceai PMID:25741868

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