Classification rationale

BA1BP4 Benign

NF1 c.*4T>C unknown · exon 58

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. BP4 (supporting): SpliceAI predicts no splice impact for this 3' UTR variant (max delta 0.004). Overall: Benign, combining stand-alone BA1 with supporting BP4 under the generic ACMG/AMP 2015 framework.

BA1 + BP4 → Benign

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

NF1 NM_001042492.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 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 · 2

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

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.

The applicable framework is ClinGen Neurofibromatosis and Schwannomatosis Expert Panel NF1 specification version 1.0.gnomAD v4.1: overall AF 0.1144% (1,847/1,613,986), South Asian AF 1.9147% (1,744/91,084), 22 South Asian homozygotes, and South Asian grpmax FAF 1.8399%.gnomAD v2.1 independently reports South Asian AF 2.0123% (616/30,612), 6 South Asian homozygotes, and grpmax FAF 1.8808%.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): SpliceAI predicts no splice impact, with max delta score 0.004, consistent with a benign effect.

SpliceAI Lookup: DS_AG=0.00, DS_AL=0.001, DS_DG=0.00, DS_DL=0.004, max delta=0.004 for NM_001042492.2:c.*4T>C, indicating no predicted disruption of splice donor/acceptor sites.Variant lies in the 3' UTR, 4 nt beyond the stop codon; no missense change is created, so REVEL/BayesDel/aGVGD computational missense evidence does not apply here.

spliceai ↗

Assessed · not applied · 2 not met · 13 not assessed

Pathogenic

PS2 Not assessed: no de novo occurrence with parental confirmation or proband phenotype data was reported.

PS3 Not assessed: no functional assay data (splicing, RNA, or protein) for this variant were available.

PS4 Not assessed: no case-control or affected-series enrichment data for this exact variant were available.

PM2 Not met: the allele is common in population databases, with South Asian gnomAD v4.1 frequency 1.91%.

PM6 Not assessed: no presumed de novo occurrence in an affected individual was reported.

PP1 Not assessed: no family segregation data, affected-relative genotypes, or meiosis counts were available.

PP3 Not met: SpliceAI max delta 0.004, far below the ~0.2 threshold used to flag splice impact.

PP4 Not assessed: no NF1-specific proband phenotype data were provided.

PP5 Not assessed: no expert-panel record classifies this exact variant as pathogenic or likely pathogenic.

Benign

BS2 Not assessed: the 22 reported homozygotes were not confirmed as comprehensively phenotyped and unaffected.

BS3 Not assessed: no functional assay data refuting a damaging effect for this variant were available.

BS4 Not assessed: no unaffected-carrier or affected-non-carrier genotypes or pedigree data were available.

BP2 Not assessed: no individual-level co-occurrence or phased trans observations were available.

BP5 Not assessed: no evidence of an alternate cause of the phenotype was available.

BP6 Not assessed: no expert-panel record classifies this exact variant as benign or likely benign.

N/A · 11 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BS1 · BP1 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00114437; MAF= 0.11444%, 1847/1613986 alleles, homozygotes = 22) and has highest observed frequency in the South Asian population (AF= 0.0191472; MAF= 1.91472%, 1744/91084 alleles, homozygotes = 22); grpmax FAF= 0.0183991.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00222805; MAF= 0.22281%, 630/282758 alleles, homozygotes = 6) and has highest observed frequency in the South Asian population (AF= 0.0201228; MAF= 2.01228%, 616/30612 alleles, homozygotes = 6); grpmax FAF= 0.0188075.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.001954185213331886, 36/18422 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.11% · 1847 / 1,613,986
22 hom · FAF 1.8%

South Asian 1744 / 91,084	1.9% 22 hom
Remaining individuals 88 / 62,502	0.14%
Middle Eastern 3 / 6,056	0.05%
African/African American 7 / 75,018	0.0093%
East Asian 2 / 44,876	0.0045%
European (non-Finnish) 3 / 1,179,914	0.00025%

+ 4 not observed (Admixed American, European (Finnish), Amish, Ashkenazi Jewish)

gnomAD v2.1

0.22% · 630 / 282,758
6 hom · FAF 1.9%

South Asian 616 / 30,612	2% 6 hom
Remaining individuals 10 / 7,224	0.14%
African/African American 2 / 24,956	0.008%
East Asian 1 / 19,948	0.005%
European (non-Finnish) 1 / 129,132	0.00077%

+ 3 not observed (Admixed American, Ashkenazi Jewish, European (Finnish))

gnomAD Canada 🇨🇦

0.2% · 36 / 18,422
0 hom · FAF 1.9%

South Asian 35 / 1,362	2.6%
Remaining individuals 1 / 1,138	0.088%

+ 7 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish))

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (10 clinical laboratories) and as Likely benign (6 clinical laboratories). (ClinVarID = 184532)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

Triaged references · 11 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

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. CLINVAR

10678181 ↗ Nf1 and Gmcsf interact in myeloid leukemogenesis. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. 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

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

27069254 ↗ The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. CLINVAR

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