rs864622406

Variant names:

• chr17-31258376-C-G
• rs864622406
• NM_001042492.3:c.4206C>G
• NF1 p.Ile1402Met

Your query was ambiguous. Multiple possible variants found:

• chr17-31258376-C-G
• chr17-31258376-C-T
• chr17-31258376-C-A

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_Supporting

The NM_001042492.3(NF1):c.4206C>G (p.Ile1402Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene NF1 is a tumor suppressor gene (CancerMine: 101 TSG, 30 oncogene, 95 driver citations). The gene NF1 is a known oncogene (CancerMine: 101 TSG, 30 oncogene, 95 driver citations). The gene NF1 is a cancer driver gene (CancerMine: 101 TSG, 30 oncogene, 95 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I1402F: Uncertain_significance (ClinVar VariationId 1738171, 2 stars); p.I1402= (synonymous): Benign/Likely_benign (ClinVar VariationId 220165, 2 stars); p.I1402V: Uncertain_significance (ClinVar VariationId 3404946, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.182
• Publications: 3 publications found

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NF1 NM_001042492.3	MANE Select	c.4206C>G p.Ile1402Met	missense	Exon 32 of 58	Prot: NP_001035957.1 UniProt:
	NF1 NM_000267.4		c.4143C>G p.Ile1381Met	missense	Exon 31 of 57	Prot: NP_000258.1 UniProt:

NF1 NM_001042492.3

MANE Select

HGVSc / HGVSpc.4206C>Gp.Ile1402Met

Exon rankExon 32 of 58

missense

Prot: NP_001035957.1UniProt: P21359-1

NF1 NM_000267.4

HGVSc / HGVSpc.4143C>Gp.Ile1381Met

Exon rankExon 31 of 57

missense

Prot: NP_000258.1UniProt: P21359-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NF1 ENST00000358273.9	TSL:1MANE Select	c.4206C>G p.Ile1402Met	missense	Exon 32 of 58	Prot: ENSP00000351015.4 UniProt:
	NF1 ENST00000356175.7	TSL:1	c.4143C>G p.Ile1381Met	missense	Exon 31 of 57	Prot: ENSP00000348498.3 UniProt:
	NF1 ENST00000579081.6	TSL:1	n.4143C>G	non_coding_transcript_exon	Exon 31 of 58	Prot: ENSP00000462408.2 UniProt:

NF1 ENST00000358273.9

TSL:1MANE Select

HGVSc / HGVSpc.4206C>Gp.Ile1402Met

Exon rankExon 32 of 58

missense

Prot: ENSP00000351015.4UniProt: P21359-1

NF1 ENST00000356175.7

TSL:1

HGVSc / HGVSpc.4143C>Gp.Ile1381Met

Exon rankExon 31 of 57

missense

Prot: ENSP00000348498.3UniProt: P21359-2

NF1 ENST00000579081.6

TSL:1

HGVSc / HGVSpn.4143C>G

Exon rankExon 31 of 58

non_coding_transcript_exon

Prot: ENSP00000462408.2UniProt: J3KSB5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.86	D
FuncVEP CTI	Benign	0.086
GPN-Star LLR	N/A	-9.1
GPN-Star score	N/A	9.1
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.15	D
Mutation Taster	N/A	20/80	disease causing
MutationAssessor	Uncertain	2.1	M
PhyloP100	Benign	0.18
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.018	D
Varity_R	N/A	0.87
VESM-3B	Benign	-8.0

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs864622406;

hg19: chr17-29585394;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar