BA1 is met: allele frequency of 3.24% in the South Asian subpopulation (gnomAD v2.1) with 27 homozygotes and grpmax FAF of 3.07% far exceeds the 1% stand-alone benign threshold, establishing NM_000267.3:c.846G>A as a common population polymorphism incompatible with NF1 pathogenicity.1 BS1 is met: overall gnomAD allele frequency of 0.496% (v2.1, 1400/282340 alleles) exceeds the 0.3% strong benign threshold.2 BS2 is met: the variant is observed in 29 homozygous individuals in gnomAD v2.1 and 90 homozygous individuals in gnomAD v4.1, which is incompatible with a highly penetrant autosomal dominant disorder like NF1.3 This variant has been reported in ClinVar as Benign by 14 clinical laboratories and as Likely benign by 9 clinical laboratories, supporting BP6.4 SpliceAI predicts no significant splicing impact (max delta 0.06) and the variant is synonymous (p.Q282=) with no amino acid change, supporting BP4 and BP7.5
NF1
Final classification
Benign
NF1 c.846G>A · p.Gln282=
NF1
BA1 is met: allele frequency of 3.24% in the South Asian subpopulation (gnomAD v2.1) with 27 homozygotes and grpmax FAF of 3.07% far exceeds the 1% stand-alone benign threshold, establishing NM_000267.3:c.846G>A as a common population polymorphism incompatible with NF1 pathogenicity.
Neurofibromatosis and Schwannomatosis Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BS2 strong benign, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 stand-alone benign + 2 strong benign + 3 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BS2BP4BP6BP7
Benign
NF1 c.846G>A
BA1 + BS1 + BS2 + BP4 + BP6 + BP7
→
Benign
Gene diagram
· NM_000267.3 · variants mapped to exon structure
NF1
NM_000267.3
Fetching transcript structure from UCSC…
Applied criteria · 6 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00365706; MAF= 0.36571%, 5902/1613864 alleles, homozygotes = 90) and has highest observed frequency in the South Asian population (AF= 0.0326507; MAF= 3.26507%, 2972/91024 alleles, homozygotes = 85); grpmax FAF= 0.0316716.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00495856; MAF= 0.49586%, 1400/282340 alleles, homozygotes = 29) and has highest observed frequency in the South Asian population (AF= 0.0324229; MAF= 3.24229%, 990/30534 alleles, homozygotes = 27); grpmax FAF= 0.0307466.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.006462474204409688, 119/18414 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.37%
· 5902 / 1,613,864
90 hom · FAF 3.2%
90 hom · FAF 3.2%
South Asian 2972 / 91,024 |
3.3% 85 hom |
Middle Eastern 94 / 6,060 |
1.6% |
Ashkenazi Jewish 261 / 29,596 |
0.88% |
Remaining individuals 284 / 62,498 |
0.45% 1 hom |
European (non-Finnish) 2185 / 1,179,894 |
0.19% 4 hom |
Admixed American 59 / 59,998 |
0.098% |
African/African American 27 / 75,030 |
0.036% |
European (Finnish) 17 / 63,992 |
0.027% |
East Asian 3 / 44,860 |
0.0067% |
+ 1 not observed (Amish)
gnomAD v2.1
0.5%
· 1400 / 282,340
29 hom · FAF 3.1%
29 hom · FAF 3.1%
South Asian 990 / 30,534 |
3.2% 27 hom |
Ashkenazi Jewish 91 / 10,362 |
0.88% |
Remaining individuals 29 / 7,208 |
0.4% 1 hom |
European (non-Finnish) 243 / 128,874 |
0.19% 1 hom |
Admixed American 27 / 35,382 |
0.076% |
African/African American 11 / 24,948 |
0.044% |
European (Finnish) 7 / 25,092 |
0.028% |
East Asian 2 / 19,940 |
0.01% |
gnomAD Canada 🇨🇦
0.65%
· 119 / 18,414
0 hom · FAF 3.5%
0 hom · FAF 3.5%
South Asian 60 / 1,362 |
4.4% |
Remaining individuals 14 / 1,138 |
1.2% |
Middle Eastern 1 / 144 |
0.69% |
Ashkenazi Jewish 4 / 830 |
0.48% |
European (non-Finnish) 39 / 11,736 |
0.33% |
East Asian 1 / 1,338 |
0.075% |
+ 3 not observed (African/African American, Latino/Admixed American, European (Finnish))
ClinVar
This variant has been reported in ClinVar as Benign (14 clinical laboratories) and as Likely benign (9 clinical laboratories). (ClinVarID = 184123)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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; COSV62201020, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 11 PMIDs not cited in assessment
10862084 ↗
Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.
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
15060124 ↗
Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11-17 distinct from the GAP related domain.
CLINVAR
15863657 ↗
Pitfalls of automated comparative sequence analysis as a single platform for routine clinical testing for NF1.
CLINVAR
24893135 ↗
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
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