Variant classification summary

NM_001042492.2:c.4836-2A>G

NF1 · NP_001035957.1:p.? · NM_001042492.2

GRCh37: chr17:29652836 A>G · GRCh38: chr17:31325818 A>G

Gene: NF1 Transcript: NM_001042492.2

Final call

Pathogenic

PVS1 very strong PM2 moderate PM6 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.?

gnomAD AF

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

PM2 (Moderate): the variant is absent from gnomAD v2.1 and v4.1.

3

PM6 (Supporting): de novo origin reported by one ClinVar submission, unconfirmed by parental testing.

4

Overall classification: Pathogenic — PVS1 + PM2 + PM6 under generic ACMG/AMP 2015 rules.

Final determination: 1 PVS1 + 1 PM + 1 PP -> Pathogenic under generic ACMG/AMP 2015 rules.

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	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 pvs1_gene_context pvs1_generic_framework spliceai cspec
PS1	N/A	Not applicable: this splice-site variant produces no amino acid change (p.?) to compare against a previously established pathogenic missense.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: a ClinVar submission reports de novo origin, but parental genotypes and parentage confirmation are absent.	clinvar
PS3	Not assessed	Not assessed: no validated functional assay data (RNA, minigene, or protein-function) for this variant were available.
PS4	Not assessed	Not assessed: no case-control study or enrichment statistic for this exact variant was available.	clinvar cspec
PM1	N/A	Not applicable: PM1 evaluates missense variants, and this splice-site variant produces no altered amino acid to assess.	generic_acmg_combination_rules
PM2	Met	Met (Moderate): the variant is absent from gnomAD v2.1 and v4.1, so no population allele frequency supports a benign role.	cspec gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	N/A	Not applicable: neurofibromatosis type 1 is autosomal dominant, so the recessive trans-compounding criterion does not apply.	cspec PMID:25741868
PM4	N/A	Not applicable: no protein length change results from this splice-site variant, leaving nothing for PM4 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: this splice-site variant produces no missense change, so no same-residue pathogenic comparison is possible.	generic_acmg_combination_rules
PM6	Met	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
PP1	Not assessed	Not assessed: no familial genotypes, phenotypes, or cosegregation data were available.
PP2	N/A	Not applicable: PP2 evaluates missense variants, and this splice-site variant produces no missense change.	generic_acmg_combination_rules
PP3	N/A	Not applicable: SpliceAI predicts strong acceptor loss (max delta 0.989), but this same splice-prediction evidence is already captured under PVS1, so PP3 would double-count it.	spliceai pvs1_variant_assessment pvs1_generic_framework
PP4	Not assessed	Not assessed: no individual-level phenotype data for the tested person were available.	cspec clinvar
PP5	Not met	Not met: only clinical-laboratory submissions exist in ClinVar for this exact variant; no expert-panel assertion supports PP5.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency exceeds that expected for NF1.	cspec gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not met	Not met: no healthy adult carriers of this variant are reported, so the benign-observation criterion cannot be met.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no functional assay data of any kind for this variant were available.
BS4	Not assessed	Not assessed: no family data showing unaffected carriers or affected non-carriers were available.
BP1	N/A	Not applicable: BP1 evaluates missense variants, and this splice-site variant produces no missense change.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no observation of this variant in trans with a pathogenic variant was available.	cspec PMID:25741868
BP3	N/A	Not applicable: this splice-site variant does not alter protein length in a repetitive region, leaving nothing for BP3 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI predicts a strong splice-altering effect (max delta 0.989), the opposite direction of a benign-supporting prediction.	spliceai bayesdel
BP5	Not assessed	Not assessed: no alternate molecular diagnosis fully explaining the phenotype was documented.	clinvar cspec
BP6	Not met	Not met: ClinVar contains no expert-panel benign assertion for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, and this splice-site variant alters the encoded protein sequence.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.