rs587781807

Variant names:

• chr17-31226459-AC-A
• rs587781807
• NM_001042492.3:c.2033delC

Your query was ambiguous. Multiple possible variants found:

• chr17-31226459-AC-A
• chr17-31226459-AC-ACC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001042492.3(NF1):​c.2033delC​(p.Pro678ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P678P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 3.31

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-31226459-AC-A is Pathogenic according to our data. Variant chr17-31226459-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 428991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31226459-AC-A is described in Lovd as [Pathogenic]. Variant chr17-31226459-AC-A is described in Lovd as [Pathogenic]. Variant chr17-31226459-AC-A is described in Lovd as [Pathogenic]. Variant chr17-31226459-AC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2033delC	p.Pro678ArgfsTer10	frameshift_variant	Exon 18 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2033delC	p.Pro678ArgfsTer10	frameshift_variant	Exon 18 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2033delC	p.Pro678ArgfsTer10	frameshift_variant	Exon 18 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461454 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Apr 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.2033del; p.Pro678ArgfsTer10 variant (rs587781807, ClinVar ID: 428991) is reported in the literature in two individuals affected with neurofibromatosis type 1 (Fahsold 2000, Wimmer 2007), one individual with pancreatic cancer (Hu 2018), and one individual with breast cancer (Palmer 2020). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this 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 Mar;66(3):790-818. PMID: 10712197. Hu C et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. 2018 Jun 19;319(23):2401-2409. PMID: 29922827. Palmer JR et al. Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women. J Natl Cancer Inst. 2020 Dec 14;112(12):1213-1221. PMID: 32427313. Wimmer K et al. Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption. Hum Mutat. 2007 Jun;28(6):599-612. PMID: 17311297. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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); Observed in an individual with breast cancer (Palmer et al., 2020); This variant is associated with the following publications: (PMID: 25074460, 14722917, 10712197, 17311297, 22155606, 12522551, 30612635, 32427313) -

Mar 28, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. This variant has been identified in at least one individual with clinical features associated with NF1. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neurofibromatosis, type 1 Pathogenic:3

Dec 03, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria: PVS1, PS4_moderate, PM6 -

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 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.Pro678Argfs*10) 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: 17311297, 21520333; internal data). ClinVar contains an entry for this variant (Variation ID: 428991). For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Nov 24, 2023

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PM1,PP5 -

NF1-related disorder Pathogenic:1

May 01, 2024

Swedish National ChiCaP Initative, Genomic Medicine Sweden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile myelomonocytic leukemia Pathogenic:1

Jul 26, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 23, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thec.2033delCpathogenic mutation, located in codingexon18 of theNF1gene, results from a deletion of one nucleotide at position 2033, causing a translationalframeshiftwith a predicted alternate stopcodon. This alteration has previously been identified in individuals with clinical features consistent with neurofibromatosis type 1 (NF1) (Fashold et al. Am. J. Hum. Genet. 2000; 66(3):790-818; Wimmer et al.Hum. Mutat. 2007; 28(6):599-612; Pasmant et al. Eur. J. Hum. Genet. 2014; 23(5):596-601 ).In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alterationis interpreted as a disease-causing mutation (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587781807; hg19: chr17-29553477;