NM_000267.3:c.4270-9A>T is an intronic substitution located at position -9 of the intron 32 splice acceptor site in NF1.1 The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (7/1,541,860 alleles, AF = 0.00045%, no homozygotes), satisfying PM2_supporting.2 SpliceAI predicts no splicing impact (max delta score = 0.00), supporting BP4_supporting.3 A reputable clinical laboratory (Labcorp Genetics/Invitae) has classified this variant as Likely benign in ClinVar (Variation ID: 849602), satisfying BP6_supporting.4 No pathogenic criteria were met. PVS1 is not applicable as the variant is outside canonical splice sites and SpliceAI predicts no impact. No de novo (PS2/PM6), functional (PS3/BS3), segregation (PP1/BS4), or case-control (PS4) evidence was identified for this variant.5 With three supporting benign criteria (PM2_supporting, BP4_supporting, BP6_supporting) and no pathogenic criteria met, the variant is classified as Likely Benign per generic ACMG/AMP 2015 combination rules.6
NF1
Final classification
Likely Benign
NF1 c.4270-9A>T · p.?
NF1
NM_000267.3:c.4270-9A>T is an intronic substitution located at position -9 of the intron 32 splice acceptor site in NF1.
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.4270-9A>T
PM2 + BP4 + BP6
→
Likely Benign
1
pvs1_variant_assessment
6
generic_acmg_combination_rules
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
Population frequency
Overall AF
7 / 1,541,860
0.00045%
Highest · European (non-Finnish)
0.00062%
Homozygotes
0
grpmax FAF
0.00026%
Allele frequency by ancestry — gnomAD v4.1
observed in 1 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 7 / 1,121,574 | 0.00062% | 0 |
| Admixed American | 0 / 58,406 | — | — |
| European (Finnish) | 0 / 62,288 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,176 | — | — |
| Middle Eastern | 0 / 5,188 | — | — |
| South Asian | 0 / 87,348 | — | — |
| Ashkenazi Jewish | 0 / 28,618 | — | — |
| African/African American | 0 / 73,710 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 4.53997e-06; MAF= 0.00045%, 7/1541860 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.24123e-06; MAF= 0.00062%, 7/1121574 alleles, homozygotes = 0); grpmax FAF= 2.6e-06.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
Literature · 12 PMIDs triaged · 8 high-priority
12papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
15604628 ↗
case observation
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in
PP5PS4
17636453 ↗
case observation
Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors.
The objective of this document is to provide recommendations for the genetic counseling of patients and families undergoing evaluation for neurofibromatosis type 1 (NF1) or who have received a diagnosis of NF1. These recommendations are the opinions of a multi-center working group of genetic counselors with expertise in the care of individuals with NF1. These recommendations are based on the commi
PP5PS4
20065170 ↗
case observation
American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
PP5PS4
20664475 ↗
case observation
The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.
Pheochromocytomas, intra-adrenal paraganglioma, and extra-adrenal sympathetic and parasympathetic paragangliomas are neuroendocrine tumors derived from adrenal chromaffin cells or similar cells in extra-adrenal sympathetic and parasympathetic paraganglia, respectively. Serious morbidity and mortality rates associated with these tumors are related to the potent effects of catecholamines on various
PP5PS4
26324357 ↗
case observation
American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.
The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care. ASCO released its first statement on genetic testing in 1996 and updated that statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer Prevention and Ethics Committees of
PP5PS4
32602153 ↗
case observation
Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis-Practice Resource of the National Society of Genetic Counselors.
The goal of this practice resource is to provide genetic counselors and other healthcare professionals with a resource to reference when providing genetic counseling services to individuals and families undergoing evaluation for neurofibromatosis (NF) or who have received a diagnosis of NF, including NF1, NF2, and schwannomatosis. This resource represents the opinions of a multi-center working gro
PP5PS4
24893135 ↗
background review
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
PP5PS4
26140447 ↗
background review
Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PP5PS4
33939658 ↗
background review
The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.
PP5PS4
Sources & reference links