rs267606600

chr17-31219017-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001042492.3(NF1):c.1541_1542del(p.Gln514ArgfsTer43) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000031 in 1,612,716 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. Q514Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 4.30

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 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 17-31219017-CAG-C is Pathogenic according to our data. Variant chr17-31219017-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31219017-CAG-C is described in Lovd as [Pathogenic]. Variant chr17-31219017-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1541_1542del	p.Gln514ArgfsTer43	frameshift_variant	14/58	ENST00000358273.9
NF1	NM_000267.3	c.1541_1542del	p.Gln514ArgfsTer43	frameshift_variant	14/57
NF1	NM_001128147.3	c.1541_1542del	p.Gln514ArgfsTer43	frameshift_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1541_1542del	p.Gln514ArgfsTer43	frameshift_variant	14/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151798 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460918 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 726702

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151798 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74106

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000952

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 04, 2021	The NF1 c.1541_154delAG (p.Gln514ArgfsTer43) variant is a recurrent deletion predicted to result in a frameshift and premature termination or absence of the protein. Across a selection of the available literature, the p.Gln514ArgfsTer43 variant has been identified in at least eight affected individuals in a heterozygous state (Robinson et al. 1996; Sabbagh et al. 2013; Cali et al. 2017). This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the predicted truncating nature of the variant and application of ACMG criteria, the p.Gln514ArgfsTer43 variant is classified as pathogenic for neurofibromatosis, type 1. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This sequence change creates a premature translational stop signal (p.Gln514Argfs*43) 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: 8664912, 17311297, 17914445, 18546366, 25788518, 26969325). ClinVar contains an entry for this variant (Variation ID: 346). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 05, 2021	PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics, University of Zurich	May 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Dec 20, 2019	- -

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 27, 2020	The variant results in a shift of the reading frame, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 08, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	NF1: PVS1, PS2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2022	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); This variant is associated with the following publications: (PMID: 22155606, 28891274, 28152038, 30104415, 32581362, 19738042, 8664912, 21354044, 27838393, 14722917, 24676424, 19142971, 26969325, 28955729, 29849115, 29909963, 25788518, 18546366, 29079545, 27284375, 31201679, 31717729, 32575496, 31370276, 33443663, 31776437) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 27, 2020	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 14, 2023	PP4, PM2, PM6_supporting, PS4_moderate, PVS1 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 10, 2014	The c.1541_1542delAG pathogenic mutation, located in coding exon 14 of the NF1 gene, results from a deletion of two nucleotides between nucleotide positions 1541 and 1542, causing a translational frameshift with a predicted alternate stop codon. <span style="background-color:initial">This mutation has been described to occurde novoin several NF1 patients in the literature, indicating the recurrent nature of this mutation (Ars E et al. J. Med. Genet. 2003 Jun;40(6):e82 and Robinson et al.Hum. Mutat.<span style="background-color:initial">1996 ;7(1):85-8<span style="background-color:initial">).<span style="background-color:initial"><span style="background-color:initial">In addition to the clinical data presented in the literature, s<span style="background-color:initial">ince frameshifts 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). -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 05, 2019

The NF1 c.1541_1542delAG; p.Gln514fs variant (rs267606600) is reported in the medical literature in individuals and families affected with neurofibromatosis type 1 (Anastasaki 2015, Anastasaki 2017, Ars 2003, Brems 2009, De Schepper 2008, Hutter 2016, Lin 2018, Noe 2018, Ponti 2016, Pros 2008, Robinson 1996, Wang 2018, Whitworth 2018, Wimmer 2007). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 346), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Gln514fs variant is considered to be pathogenic. References: Anastasaki C et al. Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning. Hum Mol Genet. 2015 Jun 15;24(12):3518-28. Anastasaki C et al. Children with 5'-end NF1 gene mutations are more likely to have glioma. Neurol Genet. 2017 Sep 22;3(5):e192. Ars E et al. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet. 2003 Jun;40(6):e82. Brems H et al. Glomus tumors in neurofibromatosis type 1: genetic, functional, and clinical evidence of a novel association. Cancer Res. 2009 Sep 15;69(18):7393-401. De Schepper S et al. Somatic mutation analysis in NF1 cafe au lait spots reveals two NF1 hits in the melanocytes. J Invest Dermatol. 2008 Apr;128(4):1050-3. Hutter S et al. No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients. Hum Genet. 2016 May;135(5):469-75. Lin F et al. THSD7A-associated membranous nephropathy in a patient with neurofibromatosis type 1. Eur J Med Genet. 2018 Feb;61(2):84-88. Noe M et al. Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1. Mod Pathol. 2018 Oct;31(10):1532-1538. Ponti G et al. Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report. Oncol Lett. 2016 Jun;11(6):3709-3714. Pros E et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008 Sep;29(9):E173-93. Robinson PN et al. Recurrent 2-bp deletion in exon 10c of the NF1 gene in two cases of von Recklinghausen neurofibromatosis. Hum Mutat. 1996;7(1):85-8. Wang X et al. Breast cancer risk and germline genomic profiling of women with neurofibromatosis type 1 who developed breast cancer. Genes Chromosomes Cancer. 2018 Jan;57(1):19-27. Whitworth J et al. Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. Am J Hum Genet. 2018 Jul 5;103(1):3-18. 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. -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 29, 2023

- -

Neurofibromatosis-Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Oct 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs267606600; hg19: chr17-29546035; COSMIC: COSV62194613;