Variant classification summary

NM_001042492.3:c.2573C>G

NF1 · NP_001035957.1:p.(Ser858Cys) · NM_001042492.3

GRCh37: chr17:29556206 C>G · GRCh38: chr17:31229188 C>G

Gene: NF1 Transcript: NM_001042492.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.3

Protein

NP_001035957.1:p.(Ser858Cys)

gnomAD AF

1.4269264748215721e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely rare in population databases, with highest allele frequency 0.00143% in gnomAD v4.1, below the 0.1% threshold.

2

BP4 (Supporting): REVEL 0.042 is at or below the benign-supporting threshold, and SpliceAI max delta 0.00 predicts no splice impact.

3

Overall classification: VUS - one pathogenic-supporting (PM2) and one benign-supporting (BP4) criterion meet no combination threshold under the generic ACMG/AMP 2015 framework.

Final determination: Under the generic ACMG/AMP 2015 fallback, one pathogenic supporting criterion and one benign supporting criterion do not satisfy any definitive classification combination and therefore result 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	Not applicable: missense substitution produces p.(Ser858Cys), so no null-variant mechanism (nonsense-mediated decay, truncation, or splice disruption) is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no validated pathogenic or likely pathogenic same-amino-acid substitution at residue 858 was available for comparison.
PS2	Not assessed	Not assessed: no de novo observation with parental testing documenting absence of the variant in both biological parents was available.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay demonstrating a deleterious effect was available.	cspec oncokb PMID:25741868 PMID:26467025
PS4	Not assessed	Not assessed: no variant-specific case-control or cohort enrichment data were available.	cspec
PM1	Not assessed	Not assessed: the authoritative NF1 domain list required for a residue-based mutational-hotspot check was unavailable.	cspec
PM2	Met	Met (Supporting): extremely rare in population databases, with highest allele frequency 0.00143% (23/1,611,856 alleles) in gnomAD v4.1, below the 0.1% threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: NF1 causes autosomal dominant disease, and PM3 requires biallelic or recessive disease evidence.	cspec
PM4	N/A	Not applicable: missense substitution causes no protein length change, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no validated pathogenic missense comparator at residue 858 was available.	pm5_candidates
PM6	Not assessed	Not assessed: no documented presumed de novo occurrence with family and phenotype details was available.	cspec
PP1	Not assessed	Not assessed: no segregation data in affected or unaffected relatives were available.	cspec
PP2	Not assessed	Not assessed: the NF1 specification provides no PP2 rule establishing missense as a common pathogenic mechanism.	cspec
PP3	Not met	Not met: REVEL 0.042 is below the pathogenic-supporting threshold, and SpliceAI max delta 0.00 predicts no splice impact.	cspec revel spliceai
PP4	Not assessed	Not assessed: no proband phenotype or phenotype-specificity evidence was provided.	cspec
PP5	Not met	Not met: no ClinVar expert-panel pathogenic or likely pathogenic classification exists for this exact variant.	clinvar
BA1	Not met	Not met: highest observed population frequency is 0.00143%, far below the 1% benign stand-alone threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest subgroup frequency is 0.00195% in gnomAD v4.1, far below the 0.3% benign-frequency threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carriers were documented, and absence of homozygotes is not positive evidence.	cspec gnomad_v4 PMID:17636453
BS3	Not assessed	Not assessed: no variant-specific functional assay demonstrating preserved NF1 function was available.	cspec oncokb PMID:25741868 PMID:26467025
BS4	Not assessed	Not assessed: no unaffected relatives carrying the variant or pedigree-based non-segregation evidence were documented.	cspec
BP1	Not assessed	Not assessed: the NF1 specification provides no BP1 rule, and missense is not established as a generally non-pathogenic mechanism in NF1.	cspec
BP2	Not assessed	Not assessed: a ClinVar note reports co-occurrence with an NF1 truncating variant, but phase (trans/cis) and individual-level records were not established.	clinvar cspec
BP3	N/A	Not applicable: missense substitution does not alter protein length in a repetitive region, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): REVEL 0.042 is at or below the benign-supporting threshold, and SpliceAI max delta 0.00 predicts no splice impact.	cspec revel spliceai
BP5	Not assessed	Not assessed: no evidence of an independently pathogenic molecular diagnosis fully explaining the phenotype was available.	clinvar
BP6	Not met	Not met: no ClinVar expert-panel benign or likely benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: this criterion applies only to synonymous variants, and this is a missense substitution.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.