Classification rationale

BS2BP4BP7 Likely Benign

NF1 c.7584A>G synonymous · exon 51

BS2 strong: gnomAD v4.1 reports six homozygotes, inconsistent with a highly penetrant autosomal-dominant NF1 allele. BP4 supporting: SpliceAI maximum delta 0.001 predicts no splice impact. BP7 supporting: the synonymous variant is outside the canonical splice consensus with minimal predicted splice impact.

BS2 + BP4 + BP7 → Likely Benign

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

NF1 NM_001042492.2

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BS2 strong review Benign

Met: gnomAD v4.1 contains 6 homozygotes, incompatible with a highly penetrant autosomal-dominant NF1 allele.

The governing NF1 framework identifies autosomal-dominant inheritance for neurofibromatosis type 1.gnomAD v4.1 reports total_hom 6, comprising 5 exome homozygotes and 1 genome homozygote, among 1578/1614034 observed alleles.The absence of individual-level phenotype and age data prevents direct confirmation of the ACMG/AMP healthy-adult wording and is the reason for human review.

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BP4 supporting Benign

Met, supporting: synonymous variant has a SpliceAI maximum delta score of 0.001, meeting the <=0.1 BP4 threshold.

The case variant is NM_001042492.2:c.7584A>G, annotated as synonymous, NP_001035957.1:p.(Gln2528=).SpliceAI is available and reports maximum delta 0.001.The supplied Jaganathan et al. 2019 calibration (PMID:30661751) defines BP4 supporting for SpliceAI max delta <=0.1.

cspec ↗spliceai ↗

BP7 supporting Benign

Met, supporting: synonymous c.7584A>G is non-canonical and has a minimal SpliceAI maximum delta score of 0.001.

The variant is synonymous, NM_001042492.2:c.7584A>G, p.(Gln2528=).The case assessment identifies the variant as outside the canonical splice consensus, and SpliceAI reports maximum delta 0.001.The ACMG/AMP guideline basis for BP7 is Richards et al. 2015 (PMID:25741868): a synonymous variant may support benign evidence when it is not expected to affect splicing.

cspec ↗spliceai ↗PMID:25741868 ↗

Assessed · not applied · 7 not met · 9 not assessed

Pathogenic

PS2 Not assessed: no confirmed parental genotypes or maternity/paternity evidence establish that c.7584A>G arose de novo in the proband.

PS3 Not assessed: no variant-specific validated functional assay or transcript result was reported for c.7584A>G (p.Gln2528=).

PS4 Not met: reviewed studies provide no exact-variant affected-case series or case-control enrichment for NF1 c.7584A>G.

PM2 Not met: gnomAD v4.1 overall AF is 0.000977675, above the 0.0001 supporting PM2 threshold.

PM6 Not assessed: no documented family testing supports even a presumed de novo origin of c.7584A>G.

PP1 Not assessed: zero informative affected-relative genotypes or meioses are documented for segregation of c.7584A>G.

PP3 Not met: synonymous variant uses SpliceAI, whose maximum delta score is 0.001, below the 0.2 PP3 supporting threshold.

PP4 Not assessed: no patient phenotype or disease-specific diagnostic features are documented for evaluating phenotype specificity.

PP5 Not met: ClinVar reports zero expert-panel submissions for the exact variant, and available laboratory labels are not eligible for PP5.

Benign

BA1 Not met: maximum observed all-comers population AF is 0.00909, below the 0.05 stand-alone threshold.

BS1 Not met: maximum observed all-comers population AF is 0.00909, below the 0.01 strong threshold.

BS3 Not assessed: no variant-specific validated assay demonstrated normal function or normal transcript processing for c.7584A>G (p.Gln2528=).

BS4 Not assessed: no informative unaffected relatives carrying c.7584A>G are documented for non-segregation.

BP2 Not assessed: no affected-proband observation with a second pathogenic variant and no reliable cis/trans phase information are documented.

BP5 Not assessed: no patient-level alternative molecular diagnosis is documented to explain the phenotype independently of this NF1 variant.

BP6 Not met: ClinVar has no exact-variant expert-panel classification, so laboratory Benign or Likely benign labels cannot 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= 0.000977675; MAF= 0.09777%, 1578/1614034 alleles, homozygotes = 6) and has highest observed frequency in the Middle Eastern population (AF= 0.00792602; MAF= 0.79260%, 48/6056 alleles, homozygotes = 0); grpmax FAF= 0.0061424.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00109648; MAF= 0.10965%, 310/282724 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00694578; MAF= 0.69458%, 72/10366 alleles, homozygotes = 0); grpmax FAF= 0.00159181.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.098% · 1578 / 1,614,034
6 hom · FAF 0.61%

Middle Eastern 48 / 6,056	0.79%
Ashkenazi Jewish 193 / 29,598	0.65% 2 hom
Admixed American 170 / 60,006	0.28%
Remaining individuals 145 / 62,496	0.23% 1 hom
European (non-Finnish) 964 / 1,179,964	0.082% 3 hom
African/African American 52 / 75,040	0.069%
East Asian 2 / 44,878	0.0045%
European (Finnish) 2 / 64,018	0.0031%
South Asian 2 / 91,066	0.0022%

+ 1 not observed (Amish)

gnomAD v2.1

0.11% · 310 / 282,724
0 hom · FAF 0.16%

Ashkenazi Jewish 72 / 10,366	0.69%
Remaining individuals 25 / 7,214	0.35%
Admixed American 69 / 35,408	0.19%
European (non-Finnish) 125 / 129,098	0.097%
African/African American 15 / 24,958	0.06%
East Asian 2 / 19,948	0.01%
European (Finnish) 1 / 25,122	0.004%
South Asian 1 / 30,610	0.0033%

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (12 clinical laboratories) and as Benign (7 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 184154)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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; COSV62204673, 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. 9 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 · 9 PMIDs not cited in assessment

23460398 ↗ Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia. CLINVAR

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

10678181 ↗ Nf1 and Gmcsf interact in myeloid leukemogenesis. CLINVAR

20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. CLINVAR

20301288 ↗ Neurofibromatosis 1. CLINVAR

26324357 ↗ American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. CLINVAR

26140447 ↗ Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. 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

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