Variant classification summary

NM_001042492.3:c.6737del

NF1 · NP_001035957.1:p.(Pro2246GlnfsTer19) · NM_001042492.3

GRCh37: chr17:29665073 AC>A · GRCh38: chr17:31338055 AC>A

Gene: NF1 Transcript: NM_001042492.3

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.3

Protein

NP_001035957.1:p.(Pro2246GlnfsTer19)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift deletion introduces a premature stop codon 19 residues downstream, predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

3

Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) reaches the Likely Pathogenic threshold under the ClinGen SVI 2020 points-based combination rule.

Final determination: 1 PVS1 (very strong) plus 1 supporting-strength criterion (PM2) meets the generic ACMG/AMP 2015 fallback combination for Likely Pathogenic per the ClinGen SVI 2020 PM2 downgrade addendum (PVS1 + 1 supporting = LP, Post_P 0.988).

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): single-nucleotide deletion creates a frameshift with a premature stop codon 19 residues downstream, predicted to trigger nonsense-mediated decay.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework PMID:10712197 PMID:10862084 PMID:23913538
PS1	N/A	Not applicable: as a frameshift variant, no altered amino acid exists to compare against a previously established pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or confirmation of a de novo occurrence was documented.	cspec
PS3	Not assessed	Not assessed: no functional assay results for this specific variant were available.
PS4	Not assessed	Not assessed: no case-control or enrichment data for this variant were available.	clinvar
PM1	N/A	Not applicable: no altered residue exists to evaluate for mutational hot-spot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare autosomal-dominant disease variant.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	Not applicable: NF1 disease is autosomal dominant, while PM3 applies to recessive disease.	cspec
PM4	N/A	Not applicable: the frameshift does not alter protein length, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a known pathogenic missense variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence with assumed or unverified parental relationships was documented.	cspec
PP1	Not assessed	Not assessed: no affected relatives or cosegregation data for this variant were documented.	cspec
PP2	N/A	Not applicable: PP2 applies to missense variants, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: not a missense or splice-region variant; SpliceAI max delta 0.177 is below the 0.2 significance threshold.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or diagnostic features were supplied for evaluation.	cspec
PP5	Not met	Not met: the ClinVar record has only a single laboratory assertion and no expert-panel submission.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, so no allele frequency reaches the stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, so no excess allele frequency exists.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no data on the variant in healthy adults were available.
BS3	Not assessed	Not assessed: no assay evidence of normal protein function for this variant was available.
BS4	Not assessed	Not assessed: no genotype or phenotype data for unaffected relatives were documented.	cspec
BP1	N/A	Not applicable: BP1 applies to missense variants, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase, parental, or trans-observation data were available.	cspec
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repetitive regions, not frameshift variants.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: in-silico missense scoring does not apply to a frameshift, and splicing is not its operative mechanism.	spliceai
BP5	Not assessed	Not assessed: no evidence of an alternative cause of disease was supplied.
BP6	Not met	Not met: the ClinVar record has no expert-panel submission and its sole laboratory assertion is Pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, and this variant alters the encoded protein.	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.