Classification rationale

BA1BS1BS2BP4 Benign

NF1 c.2544G>A synonymous · exon 21

BA1 (Stand-alone): gnomAD v4.1 African/African American allele frequency 8.31% exceeds the >5% threshold. 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. BS2 (Strong): 310 homozygotes in gnomAD v4.1 despite NF1's near-complete penetrance by adulthood. BP4 (Supporting): SpliceAI max delta 0.079, below the 0.1 threshold for predicted splice impact. Overall: Benign — BA1 alone is sufficient under the generic ACMG/AMP 2015 rules, with two BS criteria independently satisfied as well.

BA1 + BS1 + BS2 + BP4 → 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: gnomAD v4.1 African/African American allele frequency 8.31% exceeds the >5% stand-alone benign threshold.

ACMG/AMP 2015 (PMID:25741868): 'In general, an allele frequency in a control population that is greater than expected for the disorder (Table 6) is considered strong support for a benign interpretation for a rare Mendelian disorder (BS1) or if over 5% then it is considered as stand-alone support (BA1).'gnomAD v4.1: AFR AF = 0.0830509 (6225/74954 alleles, 305 homozygotes), joint grpmax FAF = 0.0813264, total AF = 0.00451209 (7273/1611892) — AFR AF and grpmax FAF both exceed the >5% BA1 thresholdgnomAD v2.1: AFR AF = 0.0793638 (1976/24898 alleles, 95 homozygotes), grpmax FAF = 0.0771056, total AF = 0.00770786 (2173/281920) — AFR AF and grpmax FAF both exceed the >5% BA1 threshold

PMID:25741868 ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BS1 strong Benign

Met: gnomAD v4.1 total allele frequency 0.45%, far above the ~0.02–0.05% expected for a pathogenic NF1 allele.

ACMG/AMP 2015 (PMID:25741868): 'In general, an allele frequency in a control population that is greater than expected for the disorder (Table 6) is considered strong support for a benign interpretation for a rare Mendelian disorder (BS1) or if over 5% then it is considered as stand-alone support (BA1).'NF1 disease context: autosomal dominant, near-complete penetrance, prevalence ~1/3000 -> expected pathogenic allele frequency ~0.02-0.05%; observed gnomAD v4.1 total AF 0.0045 (0.45%) is ~10-20x expected and AFR AF 0.0831 is hundreds-fold above expectedgnomAD v2.1 total AF 0.0077 (0.77%) and AFR AF 0.0794 likewise far exceed the AF expected for NF1; gnomAD-Canada overall AF 0.0061 (0.61%) and AFR AF 0.10 corroborate

PMID:25741868 ↗gnomad_v4 ↗gnomad_v2 ↗

✓

BS2 strong Benign

Met: 310 homozygotes observed in gnomAD v4.1 despite NF1's near-complete penetrance by adulthood.

ACMG/AMP 2015 (PMID:25741868): 'Furthermore, if the disease under investigation is fully penetrant at an early age and the variant is observed in a well-documented healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) condition then this is considered strong evidence for a benign interpretation (BS2).'gnomAD v4.1: 310 homozygotes total (305 of 74954 AFR alleles), gnomAD v2.1: 95 homozygotes (all in AFR, 1976/24898 alleles), gnomAD-Canada v1.0: 5 homozygotes (112/18418 alleles) — homozygous observation of a fully penetrant dominant-disease allele at this scale strongly supports benignitygnomAD-Canada v1.0 age histogram for homozygotes shows carriers across ages 50-75 (age_hist_hom bins), consistent with healthy adult carriers

PMID:25741868 ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met: SpliceAI max delta 0.079, below the 0.1 threshold for predicted splice impact.

SpliceAI lookup (spliceai): DS_AG 0.029, DS_AL 0.079, DS_DG 0.032, DS_DL 0.016; max delta 0.079, with evidence sentence 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08)'.Generic fallback calibration (generic_acmg_combination_rules): for synonymous (non-missense) variants use SpliceAI only; 'SpliceAI max delta < 0.1 -> BP4 (supporting)'. Max delta 0.079 < 0.1, so BP4 (supporting) is met (SVI-recommended thresholds; SpliceAI tool per Jaganathan et al. 2019, PMID 30661751).NF1 VCEP CSPEC (cspec) was consulted and carries no PP3/BP4 rule payload (criteria list empty, framework_complete=false); no gene-specific BP4 assignment overrides the generic calibration.

spliceai ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no proband or parental genotype data was available to confirm or exclude a de novo occurrence.

PS3 Not assessed: no well-established functional study of this variant was available.

PS4 Not assessed: no affected-versus-control prevalence data was available; control frequencies were high.

PM2 Not met: gnomAD v4.1 total allele frequency 0.45% — the variant is neither absent nor rare.

PM6 Not assessed: no proband or parental testing data was available to assume a de novo event.

PP1 Not assessed: no family, pedigree, or segregation data was available.

PP3 Not met: SpliceAI max delta 0.079 vs the >0.2 PP3 threshold.

PP4 Not assessed: no proband phenotype or family history data was available.

PP5 Not met: no ClinVar expert-panel pathogenic classification exists; all 20 submissions are from ordinary laboratories.

Benign

BS3 Not assessed: no functional assay evidence was available; unconfirmed in silico splice prediction does not qualify.

BS4 Not assessed: no affected family members were tested, so no non-segregation observations exist.

BP2 Not assessed: no cis/trans phase data was available.

BP5 Not assessed: no proband-level data was available to establish an alternate molecular basis.

BP6 Not met: the Benign ClinVar label reflects 20 ordinary laboratory submissions, not an expert panel.

BP7 Not assessed: no conservation score (e.g., PhyloP/GERP) was available to confirm the non-conservation requirement.

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= 0.00451209; MAF= 0.45121%, 7273/1611892 alleles, homozygotes = 310) and has highest observed frequency in the African/African American population (AF= 0.0830509; MAF= 8.30509%, 6225/74954 alleles, homozygotes = 305); grpmax FAF= 0.0813264.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00770786; MAF= 0.77079%, 2173/281920 alleles, homozygotes = 95) and has highest observed frequency in the African/African American population (AF= 0.0793638; MAF= 7.93638%, 1976/24898 alleles, homozygotes = 95); grpmax FAF= 0.0771056.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.006081007709849061, 112/18418 alleles, homozygotes = 5).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.45% · 7273 / 1,611,892
310 hom · FAF 8.1%

African/African American 6225 / 74,954	8.3% 305 hom
Middle Eastern 33 / 4,430	0.74%
Remaining individuals 424 / 62,312	0.68% 4 hom
Admixed American 353 / 59,982	0.59% 1 hom
South Asian 34 / 90,986	0.037%
European (non-Finnish) 204 / 1,179,808	0.017%

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

gnomAD v2.1

0.77% · 2173 / 281,920
95 hom · FAF 7.7%

African/African American 1976 / 24,898	7.9% 95 hom
Admixed American 140 / 35,352	0.4%
Remaining individuals 18 / 7,206	0.25%
South Asian 11 / 30,610	0.036%
European (non-Finnish) 28 / 128,498	0.022%

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

gnomAD Canada 🇨🇦

0.61% · 112 / 18,418
5 hom · FAF 8.4%

African/African American 102 / 1,020	10% 5 hom
Middle Eastern 1 / 144	0.69%
Remaining individuals 5 / 1,138	0.44%
Latino/Admixed American 3 / 838	0.36%
European (non-Finnish) 1 / 11,740	0.0085%

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

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (20 clinical laboratories). (ClinVarID = 183949)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).

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; COSV62196919, n = 4 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. 7 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 · 7 PMIDs not cited in assessment

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