Variant classification summary

NM_001042492.2:c.2544G>A

NF1 · NP_001035957.1:p.(Gly848=) · NM_001042492.2

GRCh37: chr17:29556177 G>A · GRCh38: chr17:31229159 G>A

Gene: NF1 Transcript: NM_001042492.2

Final call

Benign

BA1 stand-alone benign BS1 strong BS2 strong BP4 supporting

Variant details

Gene

NF1

Transcript

NM_001042492.2

Protein

NP_001035957.1:p.(Gly848=)

gnomAD AF

0.004512088899256278 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (Stand-alone): gnomAD v4.1 African/African American allele frequency 8.31% exceeds the >5% threshold.

2

BS1 (Strong): gnomAD v4.1 total allele frequency 0.45% is roughly 10–20-fold the ~0.02–0.05% expected for a pathogenic NF1 allele.

3

BS2 (Strong): 310 homozygotes in gnomAD v4.1 despite NF1's near-complete penetrance by adulthood.

4

BP4 (Supporting): SpliceAI max delta 0.079, below the 0.1 threshold for predicted splice impact.

5

Overall: Benign — BA1 alone is sufficient under the generic ACMG/AMP 2015 rules, with two BS criteria independently satisfied as well.

Final determination: Generic ACMG/AMP 2015 fallback combination rule: BA1 (stand-alone benign, allele frequency >5%) alone classifies the variant as Benign, independently supported by two strong benign criteria (BS1 + BS2) which also satisfy the '2 BS -> Benign' rule.

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: synonymous change produces p.(Gly848=), so no null-variant mechanism (nonsense-mediated decay, truncation, splice disruption) applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: synonymous change produces no altered amino acid to compare against a previously established pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband or parental genotype data was available to confirm or exclude a de novo occurrence.	clinvar
PS3	Not assessed	Not assessed: no well-established functional study of this variant was available.	cspec clinvar spliceai PMID:25741868
PS4	Not assessed	Not assessed: no affected-versus-control prevalence data was available; control frequencies were high.	gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: synonymous change produces no altered residue to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 total allele frequency 0.45% — the variant is neither absent nor rare.	PMID:25741868 gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: NF1 is autosomal dominant, so the recessive-disorder criterion does not apply.	cspec PMID:25741868
PM4	N/A	Not applicable: synonymous change causes no protein length alteration.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband or parental testing data was available to assume a de novo event.	clinvar
PP1	Not assessed	Not assessed: no family, pedigree, or segregation data was available.	clinvar
PP2	N/A	Not applicable: synonymous change, so the gene's missense-constraint properties do not apply.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.079 vs the >0.2 PP3 threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history data was available.
PP5	Not met	Not met: no ClinVar expert-panel pathogenic classification exists; all 20 submissions are from ordinary laboratories.	clinvar cspec
BA1	Met	Met: gnomAD v4.1 African/African American allele frequency 8.31% exceeds the >5% stand-alone benign threshold.	PMID:25741868 gnomad_v4 gnomad_v2 gnomad_canada
BS1	Met	Met: gnomAD v4.1 total allele frequency 0.45%, far above the ~0.02–0.05% expected for a pathogenic NF1 allele.	PMID:25741868 gnomad_v4 gnomad_v2
BS2	Met	Met: 310 homozygotes observed in gnomAD v4.1 despite NF1's near-complete penetrance by adulthood.	PMID:25741868 gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay evidence was available; unconfirmed in silico splice prediction does not qualify.	cspec clinvar spliceai PMID:25741868
BS4	Not assessed	Not assessed: no affected family members were tested, so no non-segregation observations exist.	clinvar
BP1	N/A	Not applicable: synonymous change, so the missense-in-truncating-gene criterion does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no cis/trans phase data was available.	clinvar cspec PMID:25741868
BP3	N/A	Not applicable: synonymous change involves no in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met: SpliceAI max delta 0.079, below the 0.1 threshold for predicted splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level data was available to establish an alternate molecular basis.
BP6	Not met	Not met: the Benign ClinVar label reflects 20 ordinary laboratory submissions, not an expert panel.	clinvar cspec
BP7	Not assessed	Not assessed: no conservation score (e.g., PhyloP/GERP) was available to confirm the non-conservation requirement.	spliceai PMID:25741868 cspec

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.