17-31350209-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001042492.3(NF1):c.7348C>T(p.Arg2450*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R2450R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NF1
NM_001042492.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 2.39

Publications

23 publications found

Variant links:

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

NF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-31350209-C-T is Pathogenic according to our data. Variant chr17-31350209-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 185789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.7348C>T	p.Arg2450*	stop_gained	Exon 50 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4 link	c.7285C>T	p.Arg2429*	stop_gained	Exon 49 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.7348C>T	p.Arg2450*	stop_gained	Exon 50 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461654

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000506

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:6

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg2429*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 16835897, 16944272, 25074460). ClinVar contains an entry for this variant (Variation ID: 185789). For these reasons, this variant has been classified as Pathogenic. -

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7285C>T;p.(Arg2429*) variant creates a premature translational stop signal in the NF1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 185789; PMID: 10712197; 16944272; 16835897; 25074460) - PS4. This variant is not present in population databases (rs786202457, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2019

Medical Genetics, University of Parma

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:4

Mar 02, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -

Mar 02, 2020

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 02, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16835897, 18484666, 16944272, 14722917, 34427956, 25525159, 22108604, 15060124, 16941471, 10336779, 22155606, 28422438, 10862084, 25074460, 31370276, 10712197, 31730495, 32642735, 30290804, 30877234, 29625052, 27535533, 31776437, 35456261) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Pathogenic:1

Sep 14, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NF1 c.7348C>T; p.Arg2450Ter variant (rs786202457) is reported in the literature in multiple individuals affected with neurofibromatosis type I (Fahsold 2000, Griffiths 2007, Lee 2006). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 185789), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The variant induces an early termination codon, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Arg2450Ter variant is considered to be pathogenic. References: Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000; 66(3):790-818. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Lee MJ et al. Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Hum Mutat. 2006 Aug;27(8):832. -

Subcutaneous neurofibroma;C1860334:Lisch nodules

Pathogenic:1

Sep 28, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant tumor of urinary bladder

Pathogenic:1

Laboratory of Urology, Hospital Clinic de Barcelona

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

NF1-related disorder

Pathogenic:1

Mar 13, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NF1 c.7348C>T variant is predicted to result in premature protein termination (p.Arg2450*). This variant is alternatively referred to as c.7285C>T (p.Arg2429*) using the primary transcript NM_000267. This variant has been reported in multiple individuals with neurofibromatosis type I (Fahsold et al. 2000. PubMed ID: 10712197; Lee et al. 2006. PubMed ID: 16835897; Griffiths et al. 2007. PubMed ID: 16944272). At PreventionGenetics, we previously identified this variant in other affected patients. To our knowledge, this variant has not been reported in in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185789/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Juvenile myelomonocytic leukemia

Pathogenic:1

Jan 22, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Aug 07, 2014

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R2450* pathogenic mutation (also known as c.7348C>T) located in coding exon 50 of the NF1 gene, results from a C to T substitution at nucleotide position 7348. This changes the amino acid from an arginine to a stop codon within coding exon 50. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.91

PhyloP100

2.4

Vest4

0.98

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over