NM_000267.3:c.3118A>T

NF1 · NP_000258.1:p.(Lys1040Ter) · NM_000267.3

GRCh37: chr17:29557864 A>T · GRCh38: chr17:31230846 A>T

Gene: NF1 Transcript: NM_000267.3

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Lys1040Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of 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	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).	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to the same amino acid change as a previously established pathogenic variant. This is a nonsense (truncating) variant for which the null effect is already captured by PVS1 at very_strong strength. Applying PS1 would constitute double-counting the same molecular evidence.
PS2	Not met	No de novo observation data are available for this variant. No publications or ClinVar submissions report a confirmed de novo occurrence with both maternity and paternity confirmed.
PS3	Not met	No variant-specific functional studies were identified for NM_000267.3:c.3118A>T (p.Lys1040Ter). OncoKB curates this variant as Likely Oncogenic/Likely Loss-of-function, but this represents a knowledgebase annotation rather than primary experimental data. None of the five reviewed publications directly tested or reported functional data for this exact variant. No systematic range characterization encompassing codon 1040 was identified.	oncokb
PS4	Not met	No case-control or cohort data are available for this variant. The variant is absent from ClinVar with zero submissions, and no publication reports the variant in affected individuals versus controls.
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 framework. The NF1 VCEP specifications (Version 1.0) contain no criteria rules and an empty rule_payload, providing no definition for PS5. No applicable framework defines this criterion.
PM1	Not met	The variant at codon 1040 is not located within a well-established critical functional domain. Neurofibromin's GAP-related domain (GRD) spans approximately residues 1198-1530, and codon 1040 lies upstream of this region. Cancerhotspots.org does not identify this residue as a statistically significant hotspot. The variant's truncating effect that removes downstream domains is already captured under PVS1; applying PM1 for domain removal by truncation would constitute double-counting.
PM2	Met	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%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been established. This variant is a nonsense change (p.Lys1040Ter), not a missense variant. The PM5 candidate search confirmed no classic same-residue comparator variants are available. PM5 semantics are not applicable to nonsense variants.	pm5_candidates
PM6	Not met	No de novo observation (without confirmation of maternity and paternity) is available for this variant. No publications or ClinVar submissions report a de novo occurrence.
PP1	Not met	No co-segregation data are available. No publications report this variant segregating with disease in multiple affected family members.
PP2	N/A	PP2 applies to missense variants in genes where missense is a common disease mechanism and benign missense variation is rare. This is a nonsense (truncating) variant, not a missense change.
PP3	Not met	In silico evidence is limited and insufficient for PP3. SpliceAI predicts no significant splice impact (max delta score 0.02). BayesDel score is 0.652534, which is weakly suggestive of deleteriousness but represents a single borderline predictor. REVEL and HCI prior scores are unavailable. For a nonsense variant with established PVS1 at very_strong, the deleterious effect of protein truncation is already fully captured, and PP3 would constitute double-counting the same molecular evidence.	spliceai bayesdel
PP4	Not met	No patient phenotype or family history data are available in the case materials. Clinical information is required to assess whether the phenotype is highly specific for neurofibromatosis type 1.
PP5	Not met	This variant is absent from ClinVar with zero submissions and no classification from any submitter. No reputable source has reported this variant as pathogenic. The variant does not meet the PP5 threshold of a reputable source reporting pathogenicity without independent verification.	clinvar
BA1	Not met	This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). The allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases. The allele frequency of 0% is below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available regarding observation of this variant in healthy adult controls. The variant is absent from population databases and no case reports describe it in unaffected individuals.
BS3	Not met	No functional studies of any kind were identified for this variant. There are no experimental data demonstrating a neutral or benign functional effect for NM_000267.3:c.3118A>T.
BS4	Not met	No segregation data are available. No publications report lack of segregation of this variant with disease in affected families.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a nonsense (truncating) variant, which is the established disease mechanism for NF1.
BP2	Not met	No data are available regarding the phase of this variant relative to other NF1 variants. No observation in trans with a known pathogenic variant or in cis with a pathogenic variant has been reported.
BP4	Not met	Multiple lines of computational evidence do not support a benign interpretation. SpliceAI predicts no splice impact (max delta 0.02), but BayesDel (0.652534) weakly suggests a deleterious effect. The in silico evidence is conflicting and does not meet the BP4 threshold of multiple predictors consistently suggesting no impact.	spliceai bayesdel
BP5	Not met	No data are available regarding this variant being found in a case with an alternate molecular basis for disease. No published case reports describe this variant alongside another explanatory genetic finding.
BP6	Not met	This variant is absent from ClinVar with zero submissions. No reputable source has reported this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense change (c.3118A>T, p.Lys1040Ter), not a synonymous variant.
BP3	N/A	Skipped per instruction: trivially not applicable.
PM3	N/A	Skipped per instruction: trivially not applicable. NF1 is an autosomal dominant disorder; PM3 (in trans with pathogenic variant for recessive disorders) is not applicable.
PM4	N/A	Skipped per instruction: trivially not applicable. PM4 applies to in-frame deletions/insertions or stop-loss variants. This is a substitution (nonsense) variant.

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