Variant classification summary

NM_001042492.2:c.2190C>G

NF1 · NP_001035957.1:p.(Asn730Lys) · NM_001042492.2

GRCh37: chr17:29553641 C>G · GRCh38: chr17:31226623 C>G

Gene: NF1 Transcript: NM_001042492.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.(Asn730Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

2

BP4 (Supporting): SpliceAI max delta 0.002 and REVEL 0.06 both predict a benign effect.

3

Classification: VUS - PM2 and BP4 at supporting strength are insufficient to reach the pathogenic or benign thresholds under the generic ACMG/AMP 2015 combination rules.

Final determination: 1 PM supporting + 1 BP supporting satisfies no Pathogenic/LP/Benign/LB threshold under generic ACMG combining rules -> 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	Not applicable: this is a missense substitution, so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no ClinVar record exists for this variant or any alternate codon producing p.Asn730Lys.	clinvar
PS2	Not assessed	Not assessed: no proband de novo observation or parental genotype data was available.	cspec
PS3	Not assessed	Not assessed: no functional assay data (e.g., Ras-GAP activity) for this variant was available.
PS4	Not assessed	Not assessed: no affected-case series or case-control enrichment data was available.	cspec
PM1	Not met	Not met: residue N730 lies in the N-HEAT scaffolding domain, not the GRD/RasGAP region containing the catalytic hotspot.	oncokb cspec pvs1_gene_context
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	Not assessed	Not assessed: no second pathogenic allele, phase information, or segregation data was available.	cspec
PM4	N/A	Not applicable: missense substitution, so no protein length change occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at Asn730 previously established as pathogenic was available.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no case report documenting the variant as presumed de novo was available.	cspec
PP1	Not assessed	Not assessed: no affected relatives or cosegregation observations were documented.	cspec
PP2	Not met	Not met: NF1 is predominantly truncating (48% nonsense vs 13% missense in one cohort), so missense is not a common disease mechanism.	cspec pvs1_gene_context
PP3	Not met	Not met: SpliceAI max delta 0.002 and REVEL 0.06 both predict no damaging effect.	cspec spliceai revel
PP4	Not assessed	Not assessed: no patient phenotype or clinical features for this variant were available.	cspec
PP5	Not met	Not met: the variant is absent from ClinVar with no expert-panel classification.	clinvar
BA1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, so no allele frequency exceeds the stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, so no allele frequency exceeds a disease-specific benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observations of unaffected homozygous adults for this variant were available.
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal neurofibromin function was available.
BS4	Not assessed	Not assessed: no unaffected relatives tested for the variant were documented.	cspec
BP1	Not assessed	Not assessed: NF1 is predominantly truncating, but recurrent pathogenic missense in the GRD region prevents a reliable determination.	cspec pvs1_gene_context
BP2	Not assessed	Not assessed: no observation of the variant in cis with a pathogenic variant or phase data was available.	cspec
BP3	N/A	Not applicable: missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.002 and REVEL 0.06 both predict a benign effect.	cspec spliceai revel
BP5	Not assessed	Not assessed: no data establishing an alternative molecular cause was available.	cspec
BP6	Not met	Not met: the variant is absent from ClinVar with no expert-panel classification.	clinvar
BP7	N/A	Not applicable: missense substitution, not a synonymous variant.	generic_acmg_combination_rules

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