Variant classification summary

NM_001042492.2:c.4577+11C>G

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

GRCh37: chr17:29587544 C>G · GRCh38: chr17:31260526 C>G

Gene: NF1 Transcript: NM_001042492.2

Final call

Likely Benign

BS2 strong BP4 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.?

gnomAD AF

0.0009742601944058129 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS2 strong: gnomAD v4.1 contains six homozygotes, inconsistent with a highly penetrant autosomal-dominant NF1 risk allele.

2

BP4 supporting: SpliceAI maximum delta 0.005 is below the generic <=0.1 threshold for an intronic variant.

Final determination: Generic ACMG/AMP 2015 fallback rules support Likely Benign when one strong benign criterion is combined with one supporting benign criterion.

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	Not met	Not met: the intronic +11 variant has SpliceAI max delta 0.005 and lacks evidence of abnormal splicing, NMD, or a protein-truncating consequence.	cspec pvs1_generic_framework pvs1_variant_assessment spliceai PMID:25741868
PS1	N/A	Not applicable: the intronic c.4577+11C>G variant has protein consequence p.?, so no amino-acid substitution exists for same-change comparison.	cspec
PS2	Not assessed	Not assessed: no documented proband-parent testing or confirmed de novo event is available for NM_001042492.2:c.4577+11C>G.	cspec PMID:23460398
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or RNA/protein result demonstrates that c.4577+11C>G disrupts NF1 function or splicing.	cspec spliceai PMID:25741868
PS4	Not assessed	Not assessed: no exact-variant affected-case series or case-control enrichment statistic is available to establish increased NF1 prevalence.	cspec PMID:23460398
PM1	N/A	Not applicable: the intronic variant has no assigned protein residue, so it cannot be evaluated for location within an NF1 critical functional domain.	cspec
PM2	Not met	Not met: gnomAD v4.1 AF is 0.00097426, nearly tenfold above the generic PM2 threshold of 0.0001.	cspec gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation documents a pathogenic NF1 allele in trans with c.4577+11C>G.	cspec
PM4	N/A	Not applicable: c.4577+11C>G is intronic and has no established in-frame insertion, deletion, or protein length change.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: protein consequence p.? provides no codon or amino-acid residue for comparison with pathogenic alternate substitutions.
PM6	Not assessed	Not assessed: no report identifies NM_001042492.2:c.4577+11C>G as apparently de novo without parental confirmation.	cspec PMID:23460398
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or phenotype-consistent familial segregation are documented for this variant.	cspec
PP2	N/A	Not applicable: PP2 is restricted to missense variation, whereas c.4577+11C>G is intronic with protein consequence p.? .
PP3	Not met	Not met: SpliceAI maximum delta 0.005 is below the 0.2 supporting threshold for intronic variants.	cspec spliceai
PP4	Not assessed	Not assessed: no patient phenotype or exact-variant phenotype correlation is available to demonstrate a highly specific NF1 presentation.	cspec
PP5	Not met	Not met: exact-variant ClinVar has zero expert-panel submissions and reports laboratory classifications as benign or likely benign.	clinvar
BA1	Not met	Not met: the highest robust population frequency is 0.00792341, below the generic BA1 threshold of 0.05; the 4/52 outlier is a small-sample artifact.	cspec gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest robust population frequency is 0.00792341, below the generic BS1 threshold of 0.01.	cspec gnomad_v4
BS2	Met	Met, strong: gnomAD v4.1 contains 6 homozygotes for this allele, inconsistent with a highly penetrant autosomal-dominant NF1 risk allele.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated functional assay or RNA/protein result demonstrates normal NF1 function or splicing for c.4577+11C>G.	cspec spliceai PMID:25741868
BS4	Not assessed	Not assessed: no tested unaffected relative carrying the variant, with adequate age and phenotype information, is documented.	cspec
BP1	N/A	Not applicable: BP1 concerns benign missense variation, but this intronic variant has no defined amino-acid change and protein consequence p.? .
BP2	Not assessed	Not assessed: no phase-resolved observation places c.4577+11C>G in trans with a pathogenic NF1 variant in an informative context.	cspec
BP3	N/A	Not applicable: this is an intronic single-nucleotide substitution, not an in-frame insertion or deletion in a repetitive protein region.	cspec pvs1_variant_assessment
BP4	Met	Met at supporting strength: SpliceAI maximum delta 0.005 is below the <=0.1 BP4 threshold for intronic variants.	cspec spliceai
BP5	Not assessed	Not assessed: no exact-variant affected case with a confirmed alternative molecular explanation is documented.	cspec clinvar
BP6	Not met	Not met: exact-variant ClinVar has zero expert-panel submissions, so laboratory Benign or Likely benign assertions cannot trigger BP6.	clinvar
BP7	N/A	Not applicable: the variant is intronic, whereas BP7 applies only to synonymous variants.

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.