Classification rationale

PVS1PM2PM6 Pathogenic

NF1 c.4836-2A>G canonical_splice · exon 36i

PVS1 (Very Strong): disruption of the canonical splice-acceptor consensus predicted to trigger nonsense-mediated decay, in a gene with an established loss-of-function mechanism. PM2 (Moderate): the variant is absent from gnomAD v2.1 and v4.1. PM6 (Supporting): de novo origin reported by one ClinVar submission, unconfirmed by parental testing. Overall classification: Pathogenic — PVS1 + PM2 + PM6 under generic ACMG/AMP 2015 rules.

PVS1 + PM2 + PM6 → Pathogenic

Gene diagram · NM_001042492.2 · variants mapped to exon structure

NF1 NM_001042492.2

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong review Pathogenic

Met (Very Strong): disruption of the canonical splice-acceptor consensus in NF1, a gene with an established loss-of-function disease mechanism, predicted to trigger nonsense-mediated decay.

pvs1_variant_assessment.json classifies this variant as consequence_class='canonical_splice', canonical_splice_consensus=true, variant_bucket='canonical_splice', and states 'This variant affects a canonical +/-1,2 splice consensus position. Under PMC6185798, canonical splice variants are evaluated with the generic PVS1 framework once germline loss of function is established for the gene...' with suggested_default_strength='PVS1'.prefetch.json variant_exonic_positions for NC_000017.10/NC_000017.11/NG_009018.1 all report start_exon='36i' and end_exon='36i', confirming the variant lies in the intron flanking exon 36 (consistent with a canonical acceptor-site position, c.4836-2).pvs1_gene_context.json states lof_mechanism_supported=true and pvs1_gene_gate='eligible', with mechanism_rationale: 'Targeted germline literature review identified disease-focused publications supporting NF1 loss of function as a germline disease mechanism, so generic PVS1 framework assessment is eligible.'

pvs1_generic_framework ↗spliceai ↗cspec ↗

✓

PM2 moderate Pathogenic

Met (Moderate): the variant is absent from gnomAD v2.1 and v4.1, so no population allele frequency supports a benign role.

gnomAD v2.1 (GRCh37 17-29652836-A-G), gnomAD v4.1 (GRCh38 chr17-31325818-A-G), and gnomAD-Canada v1.0 each report the exact variant as absent.The retrieved NF1 CSPEC material has no population-criterion rule payload, so no applicable NF1-specific PM2 strength modification was available.Richards et al. state that absence from a large general population or control cohort can be considered moderate pathogenic evidence, while noting that database read depth should be confirmed.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗PMID:25741868 ↗

✓

PM6 supporting review Pathogenic

Met (Supporting): one clinical-testing submission in ClinVar reports de novo origin. Parental genotypes and parentage confirmation are absent, so this is assumed de novo evidence pending laboratory review.

ClinVar variation 2573197 exactly matches NF1 c.4836-2A>G. SCV004015019, a single-submitter clinical-testing record, lists origin as de novo; no parental genotype or parentage-confirmation data are supplied in the case bundle.The retrieved NF1 CSPEC record has no criterion-specific content for PM6; generic ACMG/AMP PM6 logic was used for assumed, unconfirmed de novo occurrence.

clinvar ↗

Assessed · not applied · 6 not met · 9 not assessed

Pathogenic

PS2 Not assessed: a ClinVar submission reports de novo origin, but parental genotypes and parentage confirmation are absent.

PS3 Not assessed: no validated functional assay data (RNA, minigene, or protein-function) for this variant were available.

PS4 Not assessed: no case-control study or enrichment statistic for this exact variant was available.

PP1 Not assessed: no familial genotypes, phenotypes, or cosegregation data were available.

PP4 Not assessed: no individual-level phenotype data for the tested person were available.

PP5 Not met: only clinical-laboratory submissions exist in ClinVar for this exact variant; no expert-panel assertion supports PP5.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so its allele frequency of 0 is far below the >5% BA1 threshold.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency exceeds that expected for NF1.

BS2 Not met: no healthy adult carriers of this variant are reported, so the benign-observation criterion cannot be met.

BS3 Not assessed: no functional assay data of any kind for this variant were available.

BS4 Not assessed: no family data showing unaffected carriers or affected non-carriers were available.

BP2 Not assessed: no observation of this variant in trans with a pathogenic variant was available.

BP4 Not met: SpliceAI predicts a strong splice-altering effect (max delta 0.989), the opposite direction of a benign-supporting prediction.

BP5 Not assessed: no alternate molecular diagnosis fully explaining the phenotype was documented.

BP6 Not met: ClinVar contains no expert-panel benign assertion for this exact variant.

N/A · 10 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · 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

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

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 2573197)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.235399.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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 ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 7 PMIDs not cited in assessment

10712197 ↗ Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national s CLINVAR

16199547 ↗ Splicing in action: assessing disease causing sequence changes. CLINVAR

17311297 ↗ Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption. CLINVAR

17636453 ↗ Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors. CLINVAR

23913538 ↗ NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. CLINVAR

24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a CLINVAR