rs1321848637

Variant names:

• chr17-31232840-TACTC-T
• rs1321848637
• NM_001042492.3:c.3457_3460delCTCA

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.3457_3460delCTCA​(p.Leu1153MetfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L1153L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 7.62
• Publications: 9 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 17-31232840-TACTC-T is Pathogenic according to our data. Variant chr17-31232840-TACTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 185963.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.3457_3460delCTCA	p.Leu1153MetfsTer4	frameshift_variant	Exon 26 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.3457_3460delCTCA	p.Leu1153MetfsTer4	frameshift_variant	Exon 26 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3457_3460delCTCA	p.Leu1153MetfsTer4	frameshift_variant	Exon 26 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:10

Feb 03, 2021

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

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 01, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 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.Leu1153Metfs*4) 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 individuals with neurofibromatosis, type 1 (PMID: 9003501, 14517963, 18546366, 21838856, 25541118, 26969325). ClinVar contains an entry for this variant (Variation ID: 185963). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis type 1 (NF1; MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. A child can be more severely affected than the carrier parent (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported multiple times as pathogenic in ClinVar and it has been identified in individuals with NF1 (PMID: 31776437). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 20, 2019

Medical Genetics, University of Parma

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3457_3460del p.(Leu1153MetfsTer4) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. The p.(Leu1153MetfsTer4) variant has been reported in at least nine individuals with phenotypes consistent with neurofibromatosis type 1, including in a de novo state in at least one individual (PMID: 31717729; 33877690; 33674644; 34427956). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant was identified in a de novo state in the proband. Based on the available evidence, the c.3457_3460del p.(Leu1153MetfsTer4) variant is classified as pathogenic for neurofibromatosis, type 1. -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed frameshift c.3457_3460delp.Leu1153MetfsTer4 variant in NF1 gene has been reported previously in heterozygous state in individuals affected with Neurofibromatosis type I Riva et al., 2022. This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic multiple submitters. This variant causes a frameshift starting with codon Leucine 1153, changes this amino acid to Methionine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Leu1153MetfsTer4. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing Sabbagh et al., 2013. For these reasons, this variant has been classified as Pathogenic. -

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+PP1+PP4 -

not provided Pathogenic:6

Apr 25, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with neurofibromatosis 1 (PMID: 9003501 (1997), 18546366 (2008), 21838856 (2011), 31776437 (2020), 34427956 (2022)) and breast cancer (PMID: 33471991 (2021)). The variant has also been reported in a pediatric case of soft tissue sarcoma (PMID: 33674644 (2021)). Based on the available information, this variant is classified as pathogenic. -

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

- -

Aug 05, 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 in large population cohorts (gnomAD); Also known as 3456delACTC; This variant is associated with the following publications: (PMID: 23668869, 29483232, 18546366, 9003501, 14517963, 29849115, 25541118, 21838856, 24922668, 29146900, 30098238, 31776437, 31717729, 33726816, 33674644, 34427956) -

Apr 25, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3457_3460del; p.Leu1153MetfsTer4 variant (rs1321848637, ClinVar variation ID: 185963) is reported in the literature in multiple individuals affected with neurofibromatosis type 1 (selected references: Noe 2018, Upadhyaya 1997, Warejko 2018, Yao 2019), and in individuals with cancer (Kim 2021, Schwartz 2017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, 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: Kim J et al. Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study. JNCI Cancer Spectr. 2021 Jan 23;5(2):pkab007. PMID: 34308104. 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. PMID: 29849115. Schwartz JR et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun. 2017 Nov 16;8(1):1557. PMID: 29146900. Upadhyaya M et al. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. Hum Genet. 1997 Jan;99(1):88-92. PMID: 9003501. Warejko JK et al. Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ˜43% of 35 Families With Midaortic Syndrome. Hypertension. 2018 Apr;71(4):691-699. PMID: 29483232. Yao R et al. Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children. Genes (Basel). 2019 Oct 26;10(11):847. PMID: 31717729. -

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 20, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3457_3460delCTCA pathogenic mutation, located in coding exon 26 of the NF1 gene, results from a deletion of 4 nucleotides between nucleotide positions 3457 and 3460, causing a translational frameshift with a predicted alternate stop codon.<span style="background-color: initial;">This alteration has been reported in multiple unrelated patients with a clinical diagnosis of NF1, including an individual with NF1 and a malignant peripheral nerve sheath tumor diagnosed at age 25 (<span style="background-color: initial;">Pros E, Hum. Mutat. 2008 Sep; 29(9):E173-93. Kluwe L, Hum. Mutat. 2003 Nov; 22(5):420. Ponti G, Hered Cancer Clin Pract<span style="background-color: initial;">2011; 9:6)<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). -

Jan 03, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Abnormal lymph node morphology;C0235592:Cervical lymphadenopathy;C4023676:Increased nuchal translucency Pathogenic:1

Dec 13, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PM1,PM2,PP5 -

NF1-related disorder Pathogenic:1

Feb 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NF1 c.3457_3460delCTCA variant is predicted to result in a frameshift and premature protein termination (p.Leu1153Metfs*4). This variant has previously been reported in individuals with neurofibromatosis type 1 (referred to as 3456delACTC, Upadhyaya et al. 1997. PubMed ID: 9003501; Table 4, Noë et al. 2018. PubMed ID: 29849115; Warejko et al. 2018. PubMed ID: 29483232; Yao et al. 2019. PubMed ID: 31717729). 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/185963/). Frameshift variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Juvenile myelomonocytic leukemia Pathogenic:1

Dec 02, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
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: rs1321848637; hg19: chr17-29559858; COSMIC: COSV62219514;