NM_000267.3:c.3118A>T (p.Lys1040Ter) is a nonsense variant in exon 24 of the NF1 gene, predicted to result in premature termination and nonsense-mediated decay with loss of critical C-terminal functional domains including the GAP-related domain. NF1 loss-of-function is a well-established mechanism for neurofibromatosis type 1. Under the ClinGen SVI PVS1 decision framework (PMC6185798), this meets PVS1 at very_strong strength.1 This variant is absent from all queried population databases, including gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare pathogenic variant and meeting PM2 at moderate strength.2 The NF1 ClinGen VCEP specification (Version 1.0) was identified but contains no criteria-level rules. Adjudication was performed using the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868). Under generic ACMG/AMP combination rules, one Very_Strong (PVS1) plus one Moderate (PM2) supports a classification of Likely Pathogenic.3
NF1
Final classification
Likely Pathogenic
NF1 c.3118A>T · p.Lys1040Ter
NF1
NM_000267.3:c.3118A>T (p.Lys1040Ter) is a nonsense variant in exon 24 of the NF1 gene, predicted to result in premature termination and nonsense-mediated decay with loss of critical C-terminal functional domains including the GAP-related domain. NF1 loss-of-function is a well-established mechanism for neurofibromatosis type 1. Under the ClinGen SVI PVS1 decision framework (PMC6185798), this meets PVS1 at very_strong strength.
ClinGen Neurofibromatosis and Schwannomatosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NF1 Version 1.0 v1.0 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 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
NF1 c.3118A>T
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
3
generic_acmg_combination_rulescspec ↗
Gene diagram
· NM_000267.3 · variants mapped to exon structure
NF1
NM_000267.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000267.3:c.3118A>T is a nonsense variant predicted to result in premature termination at codon 1040 (p.Lys1040Ter) in exon 24 of 60. NF1 loss-of-function is a well-established disease mechanism for neurofibromatosis type 1, an autosomal dominant disorder. Nonsense-mediated decay is expected given the premature stop codon is located well upstream of the final exon-exon junction. The truncated protein loses critical C-terminal functional domains including the GAP-related domain (GRD, aa 1198-1530). No downgrade considerations apply under the ClinGen SVI PVS1 decision framework (PMC6185798).
Nonsense variant (K1040*) in exon 24 of 60NF1 loss-of-function is a well-established germline disease mechanism for neurofibromatosis type 1NMD expected — premature stop codon at aa 1040 of 2818
✓
PM2
moderate
Pathogenic
This variant is absent from all queried population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Complete absence across large population cohorts is consistent with a rare pathogenic variant and meets the PM2 threshold of allele frequency below 0.1%.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)
Assessed · not applied
Pathogenic
PS2
No de novo observation data are available for this variant.
PS3
No variant-specific functional studies were identified for NM_000267.3:c.3118A>T (p.Lys1040Ter).
PS4
No case-control or cohort data are available for this variant.
PM1
The variant at codon 1040 is not located within a well-established critical functional domain.
PM6
No de novo observation (without confirmation of maternity and paternity) is available for this variant.
PP1
No co-segregation data are available.
PP3
In silico evidence is limited and insufficient for PP3.
PP4
No patient phenotype or family history data are available in the case materials.
PP5
This variant is absent from ClinVar with zero submissions and no classification from any submitter.
Benign
BA1
This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada).
BS1
The variant is absent from all population databases.
BS2
No data are available regarding observation of this variant in healthy adult controls.
BS3
No functional studies of any kind were identified for this variant.
BS4
No segregation data are available.
BP2
No data are available regarding the phase of this variant relative to other NF1 variants.
BP4
Multiple lines of computational evidence do not support a benign interpretation.
BP5
No data are available regarding this variant being found in a case with an alternate molecular basis for disease.
BP6
This variant is absent from ClinVar with zero submissions.
N/A · 8
PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.652534.
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.
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.
Sources & reference links
9Sources
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
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