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NF1
Final classification
Likely Benign
NF1 c.4270-9A>T · p.?
NF1

NM_000267.3:c.4270-9A>T is an intronic substitution located at position -9 of the intron 32 splice acceptor site in NF1.

Gene
NF1
Transcript
NM_000267.3
HGVS · transcript:coding
NM_000267.3:c.4270-9A>T
Consequence
N/A
GRCh38
chr17:31259023 A>T
GRCh37
chr17:29586041 A>T
Basis Neurofibromatosis and Schwannomatosis Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting, BP6 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Neurofibromatosis and Schwannomatosis Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting, BP6 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2 BP4BP6 Likely Benign
NF1 c.4270-9A>T

NM_000267.3:c.4270-9A>T is an intronic substitution located at position -9 of the intron 32 splice acceptor site in NF1.1 The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (7/1,541,860 alleles, AF = 0.00045%, no homozygotes), satisfying PM2_supporting.2 SpliceAI predicts no splicing impact (max delta score = 0.00), supporting BP4_supporting.3 A reputable clinical laboratory (Labcorp Genetics/Invitae) has classified this variant as Likely benign in ClinVar (Variation ID: 849602), satisfying BP6_supporting.4 No pathogenic criteria were met. PVS1 is not applicable as the variant is outside canonical splice sites and SpliceAI predicts no impact. No de novo (PS2/PM6), functional (PS3/BS3), segregation (PP1/BS4), or case-control (PS4) evidence was identified for this variant.5 With three supporting benign criteria (PM2_supporting, BP4_supporting, BP6_supporting) and no pathogenic criteria met, the variant is classified as Likely Benign per generic ACMG/AMP 2015 combination rules.6

PM2 + BP4 + BP6 Likely Benign
1 pvs1_variant_assessment
6 generic_acmg_combination_rules
Gene diagram · NM_000267.3 · variants mapped to exon structure
NF1 NM_000267.3
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency · supports benign
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 4.53997e-06; MAF= 0.00045%, 7/1541860 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.24123e-06; MAF= 0.00062%, 7/1121574 alleles, homozygotes = 0); grpmax FAF= 2.6e-06.
      v2.1
      Absent from gnomAD v2.1.
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.00045% · 7 / 1,541,860
      0 hom · FAF 0.00026%
      European (non-Finnish)
      7 / 1,121,574
      0.00062%
      + 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
      gnomAD v2.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      Error retrieving ClinVar entry.
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Somatic evidence
      COSMIC
      This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant cancer hotspot.
      COSMIC ↗
      Sources & reference links
      7Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Triaged references · 12 PMIDs not cited in assessment
      15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
      17636453 ↗ Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors. CLINVAR
      20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. CLINVAR
      20301288 ↗ Neurofibromatosis 1. CLINVAR
      20301471 ↗ Wilms Tumor Predisposition. CLINVAR
      20664475 ↗ The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. CLINVAR
      26324357 ↗ American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. CLINVAR
      32602153 ↗ Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis-Practice Resource of the National Society of Genetic Counselors. CLINVAR
      24893135 ↗ Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. 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