rs199474754

Variant names:

• chr17-31259051-A-C
• rs199474754
• NM_001042492.3:c.4352A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-31259051-A-C
• chr17-31259051-A-G
• chr17-31259051-A-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001042492.3(NF1):​c.4352A>C​(p.Asn1451Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1451S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 8.67
• 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), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• 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: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 29 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31259050-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 569136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 17-31259051-A-C is Pathogenic according to our data. Variant chr17-31259051-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68348.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.4352A>C	p.Asn1451Thr	missense_variant	Exon 33 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.4289A>C	p.Asn1430Thr	missense_variant	Exon 32 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.4352A>C	p.Asn1451Thr	missense_variant	Exon 33 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Mar 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1430 of the NF1 protein (p.Asn1430Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with NF1-related conditions (PMID: 16380919; Invitae). ClinVar contains an entry for this variant (Variation ID: 68348). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. This variant disrupts the p.Asn1430 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12787671, 21567923, 27322474, 28422438). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1

Mar 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1430T variant (also known as c.4289A>C), located in coding exon 32 of the NF1 gene, results from an A to C substitution at nucleotide position 4289. The asparagine at codon 1430 is replaced by threonine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with neurofibromatosis type 1 (NF1) (De Luca A et al. Am J Hum Genet. 2005 Dec;77:1092-101). Other variant(s) at the same codon, p.N1430D (c.4288A>G) have been identified in individual(s) with features consistent with NF1 (Prada CE et al. Am J Med Genet A. 2011 Jun;155A:1360-6; Sabbagh A et al. Hum Mutat. 2013 Nov;34:1510-8; Evans DG et al. EBioMedicine. 2016 May;7:212-20; Santoro C et al. Am J Med Genet A. 2017 Jun;173:1521-1530). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.8	H;.;.
PhyloP100		8.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.83		Loss of stability (P = 0.0879);.;.;
MVP		0.94
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs199474754; hg19: chr17-29586069;