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NF1
Final classification
Likely Benign
NF1 c.2325+16C>G · p.?
NF1

NM_000267.3:c.2325+16C>G is an intronic variant located at position +16 in intron 19 of NF1. SpliceAI predicts no splicing impact (max delta score 0.02).

Gene
NF1
Transcript
NM_000267.3
HGVS · transcript:coding
NM_000267.3:c.2325+16C>G
Consequence
N/A
GRCh38
chr17:31227307 C>G
GRCh37
chr17:29554325 C>G
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: BP4 supporting benign, BP6 supporting benign; combination = 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: BP4 supporting benign, BP6 supporting benign; combination = 2 supporting benign, which maps to Likely Benign.
Classification rationale
BP4BP6 Likely Benign
NF1 c.2325+16C>G

NM_000267.3:c.2325+16C>G is an intronic variant located at position +16 in intron 19 of NF1. SpliceAI predicts no splicing impact (max delta score 0.02).1 This variant is present in gnomAD population databases at very low frequency: 14 of 281,840 alleles in v2.1 (AF=0.005%) and 185 of 1,612,866 alleles in v4.1 (AF=0.011%). It is absent from gnomAD-Canada.2 In ClinVar, this variant is classified as Likely benign (VariationID 512450) by 4 clinical laboratories including GeneDx, Athena Diagnostics, Genome-Nilou Lab, and Labcorp Genetics.3 No published literature was identified that directly mentions NM_000267.3:c.2325+16C>G. Eight papers from the ClinVar submission record were reviewed; all are general guidelines, methodology papers, or disease reviews that do not report this specific variant. The available evidence supports a likely benign interpretation: BP4 (SpliceAI predicts no splicing impact) and BP6 (ClinVar consensus of Likely benign from 4 clinical laboratories). No pathogenic criteria are met.4

BP4 + BP6 Likely Benign
Gene diagram · NM_000267.3 · variants mapped to exon structure
NF1 NM_000267.3
Fetching transcript structure from UCSC…
Applied criteria · 2 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= 0.000114703; MAF= 0.01147%, 185/1612866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000154364; MAF= 0.01544%, 182/1179034 alleles, homozygotes = 0); grpmax FAF= 0.00013594.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 4.96736e-05; MAF= 0.00497%, 14/281840 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.34507e-05; MAF= 0.00935%, 12/128410 alleles, homozygotes = 0); grpmax FAF= 5.412e-05.
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.011% · 185 / 1,612,866
      0 hom · FAF 0.014%
      European (non-Finnish)
      182 / 1,179,034
      0.015%
      African/African American
      2 / 74,872
      0.0027%
      Remaining individuals
      1 / 62,438
      0.0016%
      + 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
      gnomAD v2.1
      0.005% · 14 / 281,840
      0 hom · FAF 0.0054%
      European (non-Finnish)
      12 / 128,410
      0.0093%
      African/African American
      2 / 24,862
      0.008%
      + 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Likely benign (4 clinical laboratories). (ClinVarID = 512450)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
      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
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC
      Triaged references · 8 PMIDs not cited in assessment
      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
      20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. 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
      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
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR