NF1

Final classification

Likely Benign

NF1 c.4661+11A>G · p.?

NF1

Gene

NF1

Transcript

NM_000267.3

HGVS · transcript:coding

NM_000267.3:c.4661+11A>G

Consequence

N/A

GRCh38

chr17:31261868 A>G

GRCh37

chr17:29588886 A>G

Basis 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: BS3 supporting benign, BP4 supporting benign, BP6 supporting benign; combination = 3 supporting benign, which maps to Likely Benign. ▾

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: BS3 supporting benign, BP4 supporting benign, BP6 supporting benign; combination = 3 supporting benign, which maps to Likely Benign.

Classification rationale

BS3BP4BP6 Likely Benign

NF1 c.4661+11A>G

NM_000267.3:c.4661+11A>G is an intronic variant in NF1 (intron 34, +11 position) that has been observed in population databases at low frequency (gnomAD v2.1: 22/282,462 alleles, AF=0.0078%; v4.1: 281/1,612,590 alleles, AF=0.0174%).¹ Computational splicing prediction (SpliceAI, max delta = 0.10) indicates no significant impact on mRNA splicing.² A minigene splicing assay (Wimmer et al. 2007, PMID:17295913) demonstrated normal splicing of this variant with no exon skipping or cryptic splice site activation, providing functional evidence against a deleterious splicing effect (BS3_Supporting). Multiple clinical laboratories in ClinVar classify this variant as Likely benign (4 of 7 usable submissions), with no pathogenic classifications reported (BP6_Supporting).³ No pathogenic criteria are met. PVS1 is not applicable as this non-canonical intronic variant does not produce a null allele. PM2 is not met as the variant is present above absence thresholds. PS4 is not met due to population frequency inconsistent with a rare fully penetrant disorder. PS3 is not met as the only functional study shows normal splicing.⁴ Based on the available evidence (BS3_Supporting, BP4_Supporting, BP6_Supporting), this variant meets criteria for Likely benign classification. Note: BS3 is from a single minigene assay requiring verification; BP4 is from SpliceAI computational prediction; BP6 is from ClinVar clinical laboratory consensus without expert panel review.⁵

BS3 + BP4 + BP6 → Likely Benign

1 gnomad_v2 ↗gnomad_v4 ↗

2 spliceai ↗

3 clinvar ↗

4 gnomad_v2 ↗gnomad_v4 ↗pvs1_variant_assessment

5 spliceai ↗clinvar ↗

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

Benign evidence

—

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

281 / 1,612,590

0.017%

Highest · European (non-Finnish)

0.023%

Homozygotes

grpmax FAF

0.02%

Allele frequency by ancestry — gnomAD v4.1

observed in 3 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
European (non-Finnish)	268 / 1,179,810	0.023%	0
African/African American	6 / 74,876	0.008%	0
European (Finnish)	1 / 64,024	0.0016%	0
Admixed American	0 / 59,990	—	—
Amish	0 / 912	—	—
East Asian	0 / 44,852	—	—
Middle Eastern	0 / 5,148	—	—
South Asian	0 / 91,024	—	—
Ashkenazi Jewish	0 / 29,598	—	—

“

This variant is present in gnomAD v4.1 (AF= 0.000174254; MAF= 0.01743%, 281/1612590 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000227155; MAF= 0.02272%, 268/1179810 alleles, homozygotes = 0); grpmax FAF= 0.00020451.

Overall AF

22 / 282,462

0.0078%

Highest · European (non-Finnish)

0.016%

Homozygotes

grpmax FAF

0.011%

Allele frequency by ancestry — gnomAD v2.1

observed in 3 of 8 groups

Ancestry	Allele count	Frequency	Homozygotes
European (non-Finnish)	20 / 128,916	0.016%	0
Remaining individuals	1 / 7,204	0.014%	0
African/African American	1 / 24,962	0.004%	0
Admixed American	0 / 35,406	—	—
Ashkenazi Jewish	0 / 10,360	—	—
East Asian	0 / 19,902	—	—
European (Finnish)	0 / 25,106	—	—
South Asian	0 / 30,606	—	—

“

This variant is present in gnomAD v2.1 (AF= 7.78866e-05; MAF= 0.00779%, 22/282462 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00015514; MAF= 0.01551%, 20/128916 alleles, homozygotes = 0); grpmax FAF= 0.00010881.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

Error retrieving ClinVar entry.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

SpliceAI ↗

Functional No data

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

OncoKB ↗

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.

COSMIC ↗

Literature · 15 PMIDs triaged · 8 high-priority

15papers 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.

24033266 ↗ functional

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

Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a s

BS3PP5PS3PS4

25741868 ↗ functional

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.

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic

BS3PP5PS3PS4

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

20301288 ↗ case observation

Untitled reference

PP5PS4

20301471 ↗ case observation

Untitled reference

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

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

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC