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NF1
Final classification
Pathogenic
NF1 c.7039G>T · p.Glu2347Ter
NF1

NM_000267.3:c.7039G>T (p.Glu2347Ter) is a nonsense variant in NF1 exon 42 of 60 exons. NF1 loss-of-function is an established disease mechanism for neurofibromatosis type 1. The premature termination codon is predicted to trigger nonsense-mediated decay, satisfying PVS1 at very_strong strength per ClinGen SVI PVS1 recommendations (PMC6185798).

Gene
NF1
Transcript
NM_000267.3
HGVS · transcript:coding
NM_000267.3:c.7039G>T
Consequence
N/A
GRCh38
chr17:31343048 G>T
GRCh37
chr17:29670066 G>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: PVS1 very strong, PM2 supporting, PP5 supporting; combination = 1 very strong + 2 supporting, which maps to Pathogenic. ▾
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: PVS1 very strong, PM2 supporting, PP5 supporting; combination = 1 very strong + 2 supporting, which maps to Pathogenic.
Classification rationale
PVS1PM2PP5 Pathogenic
NF1 c.7039G>T

NM_000267.3:c.7039G>T (p.Glu2347Ter) is a nonsense variant in NF1 exon 42 of 60 exons. NF1 loss-of-function is an established disease mechanism for neurofibromatosis type 1. The premature termination codon is predicted to trigger nonsense-mediated decay, satisfying PVS1 at very_strong strength per ClinGen SVI PVS1 recommendations (PMC6185798).1 The variant is absent from all population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength.2 ClinVar classifies this variant as Pathogenic (GeneDx, SCV005333207, criteria provided, single submitter), meeting PP5 at supporting strength.3 Classification: Pathogenic. PVS1 (very_strong) plus PM2 (supporting) plus PP5 (supporting) satisfies the generic ACMG/AMP 2015 rule requiring 1 Very Strong and 2 Supporting criteria for a Pathogenic classification.4

PVS1 + PM2 + PP5 → Pathogenic
1 pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
3 clinvar ↗
4 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 pathogenic
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      Absent from gnomAD v4.1.
      v2.1
      Absent from gnomAD v2.1.
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      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.
      gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
      ClinVar screenshot
      ClinVar
      Error retrieving ClinVar entry.
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.652534.
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Likely Oncogenic
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      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 · 5 PMIDs not cited in assessment
      10543400 ↗ Evaluation of the protein truncation test and mutation detection in the NF1 gene: mutational analysis of 15 known and 40 unknown mutations. ONCOKB
      10862084 ↗ Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. ONCOKB
      12509763 ↗ Targeting RAS signalling pathways in cancer therapy. ONCOKB
      14722914 ↗ Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. ONCOKB
      19573811 ↗ Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. ONCOKB