Classification rationale

BA1BS1BS2BP7 Benign

NF1 c.2022C>T synonymous · exon 18

BA1 (stand-alone benign): highest population allele frequency 3.06% (African ancestry, gnomAD v4.1) exceeds the >1% threshold about 3-fold. BS1 (supporting): observed allele frequency exceeds that expected for a dominant NF1 allele by more than 150-fold. BS2 (supporting): 44 homozygotes in general-population cohorts are incompatible with a near-fully penetrant dominant disease allele. BP7 (supporting): synonymous change with no predicted splice impact (SpliceAI max delta 0.009) at a position with high population frequency. Synthesis: Benign — BA1 at stand-alone strength alone is sufficient under the generic combination rules, with BS1, BS2, and BP7 concordant and no pathogenic criterion met.

BA1 + BS1 + BS2 + BP7 → Benign

Gene diagram · NM_001042492.2 · variants mapped to exon structure

NF1 NM_001042492.2

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 15 assessed

Applied · 4

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

Met (stand-alone benign): highest population allele frequency 3.06% (African ancestry, gnomAD v4.1) exceeds the >1% BA1 threshold about 3-fold.

Applied non-VCEP gnomAD thresholds per LYFESCI/HERA v7 policy (BA1 max population AF >1%) because the NF1 CSPEC v1.0 rule payload was not available in this case bundle.gnomAD v4.1 (gnomad_v4): overall AF 0.1647% (2,658/1,613,546 alleles); highest population AF in African/African American at 3.06% (2,292/74,908 alleles); grpmax FAF 0.0296.gnomAD v2.1 (gnomad_v2): overall AF 0.2785% (785/281,884 alleles); highest population AF in African/African American at 2.89% (720/24,926 alleles); grpmax FAF 0.0269.

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗PMID:25741868 ↗cspec ↗

✓

BS1 supporting Benign

Met (supporting): observed maximum allele frequency 3.06% exceeds the ~0.01–0.02% expected for a dominant NF1 allele by over 150-fold.

Applied non-VCEP gnomAD threshold BS1 >0.3% (max population AF) per LYFESCI/HERA v7 policy; NF1 CSPEC v1.0 rule payload unavailable in this bundle.gnomAD v4.1: AFR AF 3.06%; gnomAD v2.1: AFR AF 2.89% — both >0.3% threshold by ~10-fold.Expected pathogenic-allele frequency for AD NF1 (prevalence ~1/3000, near-complete penetrance) is ~0.01-0.02%; observed overall AF 0.1647% (v4.1) is ~10x higher and observed max AF 3.06% is >150x higher (BS1 'allele frequency greater than expected for disorder', PMID:25741868).

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗PMID:25741868 ↗cspec ↗

✓

BS2 supporting Benign

Met (supporting): 44 homozygotes in gnomAD v4.1 general-population cohorts are incompatible with a near-fully penetrant dominant NF1 allele.

gnomAD v4.1 (gnomad_v4): 44 homozygotes total, 43 in African/African American (74908 AFR alleles), consistent with Hardy-Weinberg expectation at AFR AF 3% (observed 43/37,454 AFR individuals = 0.115% vs expected q^2 ~0.094%).gnomAD v2.1 (gnomad_v2): 18 homozygotes total (all in African/African American).BS2 (ACMG/AMP 2015, PMID:25741868): observed in a healthy adult individual for an autosomal dominant disorder; for a near-fully-penetrant AD disorder like NF1, homozygous presence in general-population cohorts is strong evidence against pathogenicity.

gnomad_v4 ↗gnomad_v2 ↗PMID:25741868 ↗cspec ↗

✓

BP7 supporting Benign

Met (supporting): synonymous change, no predicted splice impact (SpliceAI max delta 0.009), and high population frequency indicating no strong conservation.

Synonymous status: Mutalyzer normalization (prefetch) confirms NM_001042492.2:c.2022C>T is a synonymous variant, NP_001035957.1:p.(Ser674=).SpliceAI (spliceai) max delta score 0.009 - no impact predicted on the splice consensus sequence and no new splice site (DS_AG 0.009 acceptor gain, DS_DG 0.000 donor gain, DS_DL 0.002, DS_AL 0.002); this is below the 0.2 cutoff recommended in the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751) and below the 0.1 threshold of the lab generic calibration (generic_acmg_combination_rules).The variant is in the exon body (transcript-relative g.2406; exon spans c.2001-2250), about 22 nt from the exon's 5' end and not within any canonical splice consensus sequence; SpliceAI predicted splice-gain events are distant (DP_DG 370, DP_DL 229) with negligible delta scores.

spliceai ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no confirmed de novo occurrence with verified parentage is reported for this variant.

PS3 Not met: no functional study of this variant exists — no assay of neurofibromin activity, splicing, or RAS pathway function was found.

PS4 Not met: no case-control or NF1 case-cohort study shows enrichment; ClinVar carries only routine laboratory Benign classifications.

PM2 Not met: present at 0.16% overall and 3.06% in African ancestry in gnomAD, far above the <0.1% rarity threshold.

PM6 Not assessed: no assumed de novo occurrence is reported for this variant in any source.

PP1 Not assessed: no segregation data in affected family members were available.

PP3 Not met: SpliceAI max delta 0.009 is far below the 0.2 cutoff for predicted splice impact.

PP4 Not met: no proband with a documented NF1 phenotype carrying this exact variant is reported.

PP5 Not met: no ClinVar expert panel has classified this variant as pathogenic (zero expert-panel submissions).

Benign

BS3 Not met: no well-established functional study demonstrates absence of damaging effect; the SpliceAI prediction is in silico only.

BS4 Not assessed: no family testing data exist to establish lack of segregation in affected relatives.

BP2 Not assessed: no allelic-phase or co-occurrence data with a pathogenic variant are reported.

BP4 Not met: the only computational no-impact line (SpliceAI) is already counted under BP7 and cannot be double-counted here.

BP5 Not met: no proband-level evidence of an alternate genetic cause of disease is reported.

BP6 Not met: no expert panel has classified this variant as benign; routine laboratory consensus does not trigger BP6.

N/A · 9 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.0016473; MAF= 0.16473%, 2658/1613546 alleles, homozygotes = 44) and has highest observed frequency in the African/African American population (AF= 0.0305975; MAF= 3.05975%, 2292/74908 alleles, homozygotes = 43); grpmax FAF= 0.029553.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00278483; MAF= 0.27848%, 785/281884 alleles, homozygotes = 18) and has highest observed frequency in the African/African American population (AF= 0.0288855; MAF= 2.88855%, 720/24926 alleles, homozygotes = 18); grpmax FAF= 0.0269323.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0023894862604540022, 44/18414 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.16% · 2658 / 1,613,546
44 hom · FAF 3%

African/African American 2292 / 74,908	3.1% 43 hom
Remaining individuals 147 / 62,472	0.24% 1 hom
Admixed American 123 / 59,940	0.21%
Middle Eastern 8 / 6,056	0.13%
South Asian 11 / 91,068	0.012%
European (non-Finnish) 77 / 1,179,732	0.0065%

+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)

gnomAD v2.1

0.28% · 785 / 281,884
18 hom · FAF 2.7%

African/African American 720 / 24,926	2.9% 18 hom
Admixed American 46 / 35,352	0.13%
Remaining individuals 3 / 7,204	0.042%
South Asian 4 / 30,614	0.013%
European (non-Finnish) 12 / 128,396	0.0093%

+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD Canada 🇨🇦

0.24% · 44 / 18,414
0 hom · FAF 3%

African/African American 40 / 1,020	3.9%
Latino/Admixed American 2 / 838	0.24%
Remaining individuals 1 / 1,138	0.088%
European (non-Finnish) 1 / 11,736	0.0085%

+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (16 clinical laboratories) and as benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 141819)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104420496, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & References.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

24033266 ↗ A systematic approach to assessing the clinical significance of genetic variants. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

17636453 ↗ Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

32602153 ↗ Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis-Practice Resource of the National Society of Genetic Counselors. CLINVAR

24893135 ↗ Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

33939658 ↗ The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. CLINVAR