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.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingPM2PP3

The NM_001042492.3(NF1):c.4206C>G (p.Ile1402Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 ACMG Germline Pathogenicity v2019

Our verdict: Uncertain_significance. The variant received 4 points.

• PM1: Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 3 benign (OR vs. background: 3.6).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00122) — PM2 moderate.
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

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	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.4143C>G	p.Ile1381Met	missense	Exon 31 of 57	NP_000258.1	P21359-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.4206C>G	p.Ile1402Met	missense	Exon 32 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.4143C>G	p.Ile1381Met	missense	Exon 31 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.4143C>G		non_coding_transcript_exon	Exon 31 of 58	ENSP00000462408.2	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					32
GnomAD4 exome					31
GnomAD4 genome					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 prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	21
AlphaMissense	Benign	-	0.23
BayesDel_addAF	Pathogenic	D	0.22
BayesDel_noAF	Uncertain	-	0.070
CADD	Benign	-	21
DANN	Uncertain	-	1.0
DEOGEN2	Uncertain	D	0.66
Eigen	Uncertain	-	0.29
Eigen_PC	Uncertain	-	0.27
FATHMM_MKL	Uncertain	D	0.86
FuncVEP CTI	Benign	-	0.086
GPN-Star LLR	N/A	-	-9.1
GPN-Star score	N/A	-	9.1
LIST_S2	Uncertain	D	0.93
M_CAP	Pathogenic	D	0.85
MetaRNN	Uncertain	D	0.72
MetaSVM	Uncertain	D	0.15
Mutation Taster	N/A	disease causing	20/80
MutationAssessor	Uncertain	M	2.1
PhyloP100	Benign	-	0.18
PrimateAI	Uncertain	T	0.73
PROVEAN	Benign	N	-1.7
REVEL	Pathogenic	-	0.65
Sift	Uncertain	D	0.0040
Sift4G	Uncertain	D	0.018
Varity_R	N/A	-	0.87
VESM-3B	Benign	-	-8.0

Showing 27 of 27 scores

Splicing Scores

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

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.

Other links and lift over

dbSNP: rs864622406;

hg19: chr17-29585394;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar