Variant classification summary

NM_000267.3:c.6084+8C>G

NF1 · NP_000258.1:p.? · NM_000267.3

GRCh37: chr17:29663499 C>G · GRCh38: chr17:31336481 C>G

Gene: NF1 Transcript: NM_000267.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.?

gnomAD AF

0.002895452658450595 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000267.3:c.6084+8C>G is classified as Benign.

2

BA1 is met at stand-alone benign strength: the variant has an allele frequency of 1.43% in the Amish subpopulation of gnomAD v4.1, exceeding the >1% BA1 threshold for a highly penetrant autosomal dominant disorder (NF1 prevalence ~1/3,000). Thirteen homozygous individuals are observed in gnomAD v4.1, which is incompatible with a pathogenic NF1 variant.

3

BS1 is met at strong benign strength: the variant allele frequency of 1.43% (Amish subpopulation) far exceeds the 0.3% threshold for a dominant disorder.

4

BP4 is met at supporting benign strength: SpliceAI predicts no splice impact (max delta = 0.00), and the variant is located at the +8 intronic position, distant from the canonical splice donor site.

5

BP6 is met at supporting benign strength: ClinVar reports this variant as Benign based on 22 independent clinical laboratory submissions (11 Benign, 9 Likely benign, 1 benign).

6

BA1 is stand-alone benign. Per ACMG/AMP 2015 combination rules (Richards et al., PMID:25741868), a single BA1 criterion is sufficient for a Benign classification. The final classification is Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	N/A	This intronic variant (c.6084+8C>G, +8 position in intron 40) does not fall into any null-variant bucket (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon deletion). No protein change is predicted.	pvs1_generic_framework
PS1	N/A	This is an intronic variant with no amino acid change; same-amino-acid comparator analysis is not applicable.
PS2	Not met	No confirmed de novo observation of NM_000267.3:c.6084+8C>G has been reported in any reviewed publication or ClinVar submission.	clinvar
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect were identified. The single NF1-focused publication with full-text metadata (PMID:15060124) did not have extractable full text, and its ClinVar citation trail notes that functional studies have yet to be performed for this variant.	clinvar PMID:15060124
PS4	Not met	The variant is present at high frequency in the general population (gnomAD v4.1: AF=0.29%, 4,673 alleles; Amish subpopulation AF=1.43%), precluding statistically significant case-control enrichment for a rare Mendelian disorder.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 framework (Richards et al., PMID:25741868) and the NF1 VCEP criteria are empty with no custom PS5 specification.	PMID:25741868
PM1	N/A	This is an intronic variant with no protein residue; mutational hotspot domain analysis is not applicable.
PM2	Not met	The variant is present in population databases at appreciable frequency (gnomAD v4.1: AF=0.29%, 4,673 alleles), far exceeding the PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4
PM5	N/A	This intronic variant produces no protein change; same-residue comparator analysis is not possible. Confirmed by pm5_candidates.json: unable to parse missense residue context.	pm5_candidates
PM6	N/A	No de novo observation reported, and this intronic variant has no confirmed de novo status in any ClinVar submission or publication.	clinvar
PP1	Not met	No segregation data are available for this variant in any reviewed publication or ClinVar submission.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is an intronic variant, not a missense change.
PP3	Not met	Multiple lines of computational evidence support no splice impact. SpliceAI predicts no significant splicing alteration (max delta score = 0.00). REVEL and BayesDel are not applicable as this is an intronic variant. No in silico tools predict a deleterious effect.	spliceai
PP4	Not met	No patient-specific phenotype data are available for this variant. No case reports were identified describing affected individuals with this variant and a phenotype highly specific for NF1.
PP5	Not met	ClinVar reports this variant as Benign (22 submissions: 11 Benign, 9 Likely benign, 1 benign). No reputable source has classified this variant as pathogenic. No expert panel has reviewed this variant.	clinvar
BA1	Met	The variant has an allele frequency of 1.425% (13/912 alleles) in the Amish subpopulation in gnomAD v4.1, exceeding the 1% BA1 threshold. Additionally, 13 homozygotes are observed in gnomAD v4.1, which is incompatible with a highly penetrant autosomal dominant disorder such as NF1.	gnomad_v4
BS1	Met	The variant is present at an allele frequency of 1.425% in the Amish subpopulation of gnomAD v4.1, far exceeding the 0.3% BS1 threshold for a dominant disorder with NF1 prevalence (~1/3,000). The overall gnomAD v4.1 frequency of 0.29% also approaches this threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	No confirmed healthy adult individuals with this variant have been reported with documented unaffected status. While gnomAD contains 13 homozygotes, gnomAD does not provide individual-level phenotype confirmation, so definitive healthy status cannot be assigned from population data alone for BS2.	gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no damaging effect were identified. SpliceAI (delta=0.00) predicts no splice impact, but in silico prediction alone does not constitute well-established functional evidence required for BS3.	spliceai
BS4	Not met	No segregation data are available. Lack of segregation in affected family members cannot be assessed.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is an intronic variant, not a missense change.
BP2	Not met	No observation of this variant in trans with a known pathogenic NF1 variant has been reported.
BP3	N/A	BP3 applies to in-frame deletions/insertions; this is a single-nucleotide intronic substitution.
BP4	Met	Multiple lines of computational evidence indicate no impact on splicing or gene function. SpliceAI predicts no splicing alteration (max delta score = 0.00). The variant is located deep within intron 40 at the +8 position, away from the canonical splice donor site.	spliceai
BP5	Not met	No case has been reported where this variant is found in an individual with an alternative molecular basis for NF1-related disease.
BP6	Met	ClinVar reports this variant as Benign based on 22 submissions from multiple clinical laboratories (11 Benign, 9 Likely benign, 1 benign), though without expert panel review. Multiple independent clinical laboratories concur on a benign classification.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This is an intronic variant at +8, not a coding synonymous variant.

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.