17-31334927-C-T

Variant names:

• chr17-31334927-C-T
• rs137854552
• NM_001042492.3:c.5902C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.5902C>T​(p.Arg1968*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,670 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. R1968R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NF1 NM_001042492.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: 2.93
• Publications: 52 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 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 17-31334927-C-T is Pathogenic according to our data. Variant chr17-31334927-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 343.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	c.5902C>T	p.Arg1968*	stop_gained	Exon 40 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.5839C>T	p.Arg1947*	stop_gained	Exon 39 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5902C>T	p.Arg1968*	stop_gained	Exon 40 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461670 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727140

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 29

Alfa AF: 0.00000926 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:11

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 11, 2024

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2024

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.Arg1947*) 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 clinical features of neurofibromatosis type 1 (PMID: 2114220, 7649559, 7903661, 8069310, 8385067, 10076878; internal data). In at least one individual the variant was observed to be de novo. This variant is also known as 1087C>T and c.5902C>T (Arg1968Ter). ClinVar contains an entry for this variant (Variation ID: 343). For these reasons, this variant has been classified as Pathogenic. -

Dec 20, 2019

Medical Genetics, University of Parma

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2021

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant: PVS1, PM1, PM2, PS4 -

Mar 03, 2017

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PS4+PP4 -

not provided Pathogenic:4

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1: PVS1, PM2 -

Jan 11, 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: 15146469, 16944272, 22913777, 8845843, 9042399, 25525159, 9195229, 24232412, 1757093, 18546366, 12552569, 27322474, 22155606, 7649559, 11015700, 10721668, 7903661, 8385067, 9101300, 2114220, 26969325, 10076878, 21354044, 29178821, 28124441, 19142971, 16117786, 30290804, 31533797, 31370276, 33443663) -

Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis Pathogenic:1

Nov 10, 2018

The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

NF1-related disorder Pathogenic:1

Sep 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.5902C>T variant is predicted to result in premature protein termination (p.Arg1968*). This variant, referred to as c.5839C>T (p.Arg1947*) in an alternate transcript (NM_000267.3), has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Fashold et al. 2000. PubMed ID: 10712197; de Luca et al. 2004. PubMed ID: 15146469). To our knowledge, this variant has not been reported 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/343/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile myelomonocytic leukemia Pathogenic:1

Sep 03, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis-Noonan syndrome Pathogenic:1

Oct 23, 2023

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant NF1:c.5839C>T, p.(Arg1968*), which is located in the coding exon 40 of the NF1 gene, results from a cytosine-to-thymine substitution at nucleotide position c.5839. The arginine at protein position 1968 is replaced by a stop codon at the translational level. The variant affects and exon (40/58) that is present in biologically relevant transcripts and is predicted to cause protein truncation/absent due to non-sense mediated decay.The variant is classified as rare in the overall population (allele frequency= 0.000001859 in gnomAD v4.1.0). The variant has been consistenly classified as Pathogenic on 17 entries in ClinVar (ClinVarID: 343). In several publications, the variant has been reported as causative for neurofibromatosis (PMID: 2114220, 7649559, 12807981,10076878). Similar to previous report, the variant was detected de novo. In summary, the variant is classified as Pathogenic. -

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

Oct 14, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5839C>T (p.R1947*) alteration, located in exon 39 (coding exon 39) of the NF1 gene, consists of a C to T substitution at nucleotide position 5839. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1947. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation (also known as p.R1968* (c.5902C>T) in the NM_001042492 isoform) has been described as a recurring mutation in individuals meeting diagnostic criteria for Neurofibromatosis type 1 (NF1) (Cawthon, 1990; Fahsold, 2000; Ars, 2003; Stewart, 2014; Hutter, 2016). In addition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews, 1996). Based on the available evidence, this alteration is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 04, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1968* pathogenic mutation (also known as c.5902C>T) located in coding exon 40 of the NF1 gene, results from a C to T substitution at nucleotide position 5902. This changes the amino acid from an arginine to a stop codon within coding exon 40. This pathogenic mutation has been described as a recurring mutation in individuals with neurofibromatosis type 1 (Ars E et al. J. Med. Genet. 2003; 40:e82, Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818). In addtition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews JD et al. Hum. Mol. Genet. 1996, 5:503-7). In addition to the clinical data presented in the literature, 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). This pathogenic mutation is also known as p.R1947* (c.5839C>T) in the literature. -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		2.9
Vest4		0.99
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	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: rs137854552; hg19: chr17-29661945; COSMIC: COSV62199973; COSMIC: COSV62199973;