Variant classification summary

NM_001042492.2:c.*4T>C

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

GRCh37: chr17:29701177 T>C · GRCh38: chr17:31374159 T>C

Gene: NF1 Transcript: NM_001042492.2

Final call

Benign

BA1 stand-alone benign BP4 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.?

gnomAD AF

0.001144371760349842 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (stand-alone benign): the allele is far too common for a pathogenic NF1 allele, at ~1.9-2.0% South Asian frequency in gnomAD.

2

BP4 (supporting): SpliceAI predicts no splice impact for this 3' UTR variant (max delta 0.004).

3

Overall: Benign, combining stand-alone BA1 with supporting BP4 under the generic ACMG/AMP 2015 framework.

Final determination: Generic ACMG/AMP 2015: a single stand-alone benign criterion (BA1) is sufficient to classify a variant as Benign.

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	Not applicable: as a 3' UTR change, it alters no protein-coding sequence, creates no premature stop, and affects no splice consensus site.	pvs1_variant_assessment pvs1_gene_context gnomad_canada cspec
PS1	N/A	Not applicable: the variant produces no amino acid change, so no comparison to an established pathogenic change at the same residue is possible.
PS2	Not assessed	Not assessed: no de novo occurrence with parental confirmation or proband phenotype data was reported.
PS3	Not assessed	Not assessed: no functional assay data (splicing, RNA, or protein) for this variant were available.
PS4	Not assessed	Not assessed: no case-control or affected-series enrichment data for this exact variant were available.	cspec clinvar PMID:10678181 PMID:23460398
PM1	N/A	Not applicable: with no amino acid change, there is no residue or domain location to evaluate.
PM2	Not met	Not met: the allele is common in population databases, with South Asian gnomAD v4.1 frequency 1.91%.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: NF1 is autosomal dominant, so the recessive-disease allelic criterion does not apply.	cspec
PM4	N/A	Not applicable: no codon is deleted, inserted, or altered, so protein length is unchanged.	pvs1_variant_assessment gnomad_canada cspec
PM5	N/A	Not applicable: no amino acid substitution occurs, so there is no residue to compare with known pathogenic changes.
PM6	Not assessed	Not assessed: no presumed de novo occurrence in an affected individual was reported.
PP1	Not assessed	Not assessed: no family segregation data, affected-relative genotypes, or meiosis counts were available.
PP2	N/A	Not applicable: the criterion applies to missense variants, not 3' UTR changes.
PP3	Not met	Not met: SpliceAI max delta 0.004, far below the ~0.2 threshold used to flag splice impact.	spliceai
PP4	Not assessed	Not assessed: no NF1-specific proband phenotype data were provided.	cspec clinvar
PP5	Not assessed	Not assessed: no expert-panel record classifies this exact variant as pathogenic or likely pathogenic.	clinvar
BA1	Met	Met (stand-alone benign): South Asian allele frequency 1.91% in gnomAD v4.1 (2.01% in v2.1) is far too common for a pathogenic NF1 allele.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	N/A	Not applicable: already covered by the met BA1 population-frequency criterion, so it is not stacked.	cspec gnomad_v4
BS2	Not assessed	Not assessed: the 22 reported homozygotes were not confirmed as comprehensively phenotyped and unaffected.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay data refuting a damaging effect for this variant were available.
BS4	Not assessed	Not assessed: no unaffected-carrier or affected-non-carrier genotypes or pedigree data were available.
BP1	N/A	Not applicable: the criterion applies to missense variants, not 3' UTR changes.
BP2	Not assessed	Not assessed: no individual-level co-occurrence or phased trans observations were available.	cspec
BP3	N/A	Not applicable: the criterion requires an in-frame deletion or insertion, not a single-nucleotide substitution.	pvs1_variant_assessment gnomad_canada cspec
BP4	Met	Met (supporting): SpliceAI predicts no splice impact, with max delta score 0.004, consistent with a benign effect.	spliceai
BP5	Not assessed	Not assessed: no evidence of an alternate cause of the phenotype was available.	cspec
BP6	Not assessed	Not assessed: no expert-panel record classifies this exact variant as benign or likely benign.	clinvar
BP7	N/A	Not applicable: the variant is a 3' UTR change outside the coding sequence, not a synonymous coding 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.