NM_000267.3:c.2325+16C>G is an intronic variant located 16 bases downstream of NF1 exon 19. SpliceAI predicts no significant splicing impact (max delta score = 0.02), and the variant is not expected to alter neurofibromin function.1 This variant is observed at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.00497% (14/281,840 alleles) and gnomAD v4.1 allele frequency 0.01147% (185/1,612,866 alleles), with no homozygotes reported (PM2_Supporting).2 Multiple lines of computational evidence predict no deleterious effect: SpliceAI delta score of 0.02 indicates no significant splice alteration, and no protein-level consequence is predicted for this deep intronic change (BP4).3 This variant has been classified as Likely benign by 4 independent clinical diagnostic laboratories in ClinVar (VariationID: 512450), including GeneDx, Athena Diagnostics, Genome-Nilou Lab, and Labcorp Genetics (BP6).4 Applying the ACMG/AMP 2015 combination rules (PMID:25741868): 1 supporting pathogenic criterion (PM2_Supporting) and 2 supporting benign criteria (BP4, BP6). The preponderance of benign evidence supports classification as Likely Benign.5
NF1
Final classification
Likely Benign
NF1 c.2325+16C>G · p.?
NF1
NM_000267.3:c.2325+16C>G is an intronic variant located 16 bases downstream of NF1 exon 19. SpliceAI predicts no significant splicing impact (max delta score = 0.02), and the variant is not expected to alter neurofibromin function.
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: PM2 supporting, BP4 supporting, BP6 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP4BP6
Likely Benign
NF1 c.2325+16C>G
PM2 + BP4 + BP6
→
Likely Benign
Gene diagram
· NM_000267.3 · variants mapped to exon structure
NF1
NM_000267.3
Fetching transcript structure from UCSC…
Applied criteria · 3 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= 0.000114703; MAF= 0.01147%, 185/1612866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000154364; MAF= 0.01544%, 182/1179034 alleles, homozygotes = 0); grpmax FAF= 0.00013594.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.96736e-05; MAF= 0.00497%, 14/281840 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.34507e-05; MAF= 0.00935%, 12/128410 alleles, homozygotes = 0); grpmax FAF= 5.412e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.011%
· 185 / 1,612,866
0 hom · FAF 0.014%
0 hom · FAF 0.014%
European (non-Finnish) 182 / 1,179,034 |
0.015% |
African/African American 2 / 74,872 |
0.0027% |
Remaining individuals 1 / 62,438 |
0.0016% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.005%
· 14 / 281,840
0 hom · FAF 0.0054%
0 hom · FAF 0.0054%
European (non-Finnish) 12 / 128,410 |
0.0093% |
African/African American 2 / 24,862 |
0.008% |
+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories). (ClinVarID = 512450)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
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
Triaged references · 8 PMIDs not cited in assessment
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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
20065170 ↗
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