Classification rationale

BP7 VUS

NF1 c.1806A>G synonymous · exon 16

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

BP7 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001042492.2 · variants mapped to exon structure

NF1 NM_001042492.2

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP7 supporting Benign

Met, supporting: synonymous p.Glu602= with SpliceAI maximum delta 0.078 below the <=0.1 no-significant-splice-impact cutoff.

The case variant is synonymous: NM_001042492.2:c.1806A>G, NP_001035957.1:p.(Glu602=).SpliceAI reports DS_AG 0.078, DS_DG 0.047, DS_AL 0.0, DS_DL 0.0, with maximum delta score 0.078.The supplied generic SpliceAI calibration defines <=0.1 as the recommended no-significant-splice-impact threshold for benign computational evidence; this calibration is attributed to Jaganathan et al. 2019 (PMID:30661751).

spliceai ↗cspec ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no documented parental genotypes or confirmed de novo occurrence are available for NM_001042492.2:c.1806A>G.

PS3 Not assessed: no validated RNA, protein, or cellular assay directly evaluates NF1 c.1806A>G (p.Glu602=).

PS4 Not assessed: no exact-variant case-control enrichment, affected-case series, or odds ratio is available for NM_001042492.2:c.1806A>G.

PM2 Not met: the highest ancestry-specific allele frequency is 1.01764e-04, exceeding the generic PM2 cutoff of 0.0001.

PM6 Not assessed: no affected individual with this exact variant is documented as apparently de novo without parental testing.

PP1 Not assessed: no affected relatives, informative meioses, or family segregation data are reported for this exact variant.

PP4 Not assessed: no proband phenotype or highly specific NF1 clinical presentation is documented for this variant.

PP5 Not met: ClinVar shows 0 expert-panel submissions, and the exact-variant record contains no expert-panel Pathogenic or Likely pathogenic classification.

Benign

BA1 Not met: the highest observed allele frequency is 1.01764e-04, far below the generic BA1 threshold of 0.05.

BS1 Not met: the highest observed allele frequency is 1.01764e-04, below the generic BS1 threshold of 0.01.

BS2 Not assessed: gnomAD shows carriers but provides no documented unaffected adult status or phenotype assessment to satisfy BS2.

BS3 Not assessed: no validated assay demonstrates normal NF1 function for c.1806A>G (p.Glu602=).

BS4 Not assessed: no confirmed variant-positive unaffected relatives with reliable age-appropriate phenotyping are documented.

BP2 Not assessed: no affected-proband co-occurrence or cis/trans phase data with a pathogenic variant are documented for c.1806A>G.

BP5 Not assessed: no affected individual with this variant and a separate pathogenic explanation, or BP5-specific likelihood ratio, is documented.

BP6 Not met: ClinVar shows 0 expert-panel submissions, so non-expert Benign and Likely benign assertions cannot trigger BP6.

N/A · 11 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.59625e-05; MAF= 0.00360%, 58/1612792 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.80538e-05; MAF= 0.00481%, 3/62430 alleles, homozygotes = 0); grpmax FAF= 3.587e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.25029e-05; MAF= 0.00425%, 12/282334 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.30868e-05; MAF= 0.00931%, 12/128912 alleles, homozygotes = 0); grpmax FAF= 4.746e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0036% · 58 / 1,612,792
0 hom · FAF 0.0036%

Remaining individuals 3 / 62,430	0.0048%
European (non-Finnish) 54 / 1,179,088	0.0046%
European (Finnish) 1 / 64,010	0.0016%

+ 7 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0043% · 12 / 282,334
0 hom · FAF 0.0047%

European (non-Finnish)

12 / 128,912

0.0093%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 186321)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 11 PMIDs not cited in assessment

23460398 ↗ Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

29872168 ↗ NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome. CLINVAR

10678181 ↗ Nf1 and Gmcsf interact in myeloid leukemogenesis. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

26324357 ↗ American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. CLINVAR

26140447 ↗ Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

33939658 ↗ The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. CLINVAR

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