NM_000267.3:c.7039G>T

NF1 · NP_000258.1:p.(Glu2347Ter) · NM_000267.3

GRCh37: chr17:29670066 G>T · GRCh38: chr17:31343048 G>T

Gene: NF1 Transcript: NM_000267.3

Final call

Pathogenic

PVS1 very strong PM2 supporting PP5 supporting

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Glu2347Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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.

ClinVar classifies this variant as Pathogenic (GeneDx, SCV005333207, criteria provided, single submitter), meeting PP5 at supporting strength.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Nonsense variant NM_000267.3:c.7039G>T (p.Glu2347Ter) in exon 42 of 60 exons. NF1 loss-of-function is an established disease mechanism for neurofibromatosis type 1. The premature termination codon is located >50 nucleotides upstream of the last exon-exon junction, predicting nonsense-mediated decay. Per ClinGen SVI PVS1 recommendations (PMC6185798), nonsense variants in genes with an established LoF mechanism are assigned PVS1 at very_strong strength when NMD is predicted.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not met	PS1 applies when a different nucleotide change at the same position produces the same amino acid change and is known to be pathogenic. This is a nonsense variant; no alternative nucleotide substitution at c.7039 producing the same stop codon is reported as pathogenic.
PS2	Not met	No de novo confirmation with confirmed maternity/paternity is available for this variant in the reviewed evidence.
PS3	Not met	No well-established functional studies demonstrate a damaging effect specific to NM_000267.3:c.7039G>T. OncoKB classifies the variant as Likely Oncogenic based on curated literature context, but none of the five OncoKB-linked publications (PMID:10543400, PMID:10862084, PMID:12509763, PMID:14722914, PMID:19573811) mention this specific variant. No variant-specific functional assay data are available.	oncokb
PS4	Not met	No case-control prevalence data are available to demonstrate statistically significant enrichment of this variant in affected individuals compared to controls.
PS5	Not met	PS5 requires the same amino acid change as an established pathogenic variant via an alternative nucleotide change. No same-residue alternative nucleotide change producing p.Glu2347Ter has been identified as pathogenic in ClinVar or the reviewed literature.
PM1	Not met	This variant does not lie in a known mutational hotspot or critical functional domain as assessed by CancerHotspots.org. The variant is not in a statistically significant hotspot region.
PM2	Met	NM_000267.3:c.7039G>T is absent from all queried population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Absence from large population cohorts supports pathogenicity.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same residue. This is a nonsense variant; no same-residue pathogenic missense candidates suitable for PM5 were identified.	pm5_candidates
PM6	Not met	No de novo observation (without confirmation of paternity/maternity) has been documented for this variant in the reviewed evidence.
PP1	Not met	No co-segregation data in affected family members are available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This is a nonsense variant.
PP3	N/A	PP3 applies to missense or splice-affecting variants with in silico support for a damaging effect. This is a nonsense variant; in silico missense predictors (REVEL, BayesDel) are not relevant to the truncating mechanism. SpliceAI predicts no splicing impact (max delta 0.02).	spliceai bayesdel
PP4	Not met	No patient-specific phenotype or family history data are available to assess whether the individual's presentation is highly specific for NF1-related disease.
PP5	Met	ClinVar reports this variant as Pathogenic by a clinical testing laboratory (GeneDx, SCV005333207). Although from a single submitter with criteria provided and no expert panel review, the clinical laboratory classification supports pathogenicity.	clinvar
BA1	Not met	Allele frequency is well below 1% in all population databases. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Allele frequency is well below 0.3% in all population databases. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding observation of this variant in healthy adults in a homozygous or heterozygous state inconsistent with disease penetrance.
BS3	Not met	No well-established functional studies demonstrate no deleterious effect for this specific variant. The reviewed literature contains no variant-specific functional data for NM_000267.3:c.7039G>T.
BS4	Not met	No segregation data demonstrate lack of co-segregation with disease for this variant.
BP1	N/A	BP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease. This is a nonsense (truncating) variant.
BP2	Not met	No data are available regarding observation of this variant in trans with a known pathogenic NF1 variant.
BP4	N/A	BP4 applies to variants with multiple lines of in silico evidence suggesting no impact. This is a nonsense variant producing a premature termination codon; in silico missense predictors are not relevant. SpliceAI predicts no splicing impact (max delta 0.02), but the truncating effect supersedes this.	spliceai
BP5	Not met	No alternate molecular basis for disease has been identified that would make this variant irrelevant to the phenotype.
BP6	Not met	ClinVar classifies this variant as Pathogenic. No reputable source reports this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants. c.7039G>T is a nonsense variant producing p.Glu2347Ter.
BP3	N/A	Skipped per task instructions.
PM3	N/A	Skipped per task instructions.
PM4	N/A	Skipped per task instructions.

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