rs786202782

Variant names:

• chr17-31223475-TTAAC-T
• rs786202782
• NM_001042492.3:c.1756_1759delACTA

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.1756_1759delACTA​(p.Thr586ValfsTer18) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 8.63
• Publications: 13 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 17-31223475-TTAAC-T is Pathogenic according to our data. Variant chr17-31223475-TTAAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 186215.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.1756_1759delACTA	p.Thr586ValfsTer18	frameshift_variant	Exon 16 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.1756_1759delACTA	p.Thr586ValfsTer18	frameshift_variant	Exon 16 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1756_1759delACTA	p.Thr586ValfsTer18	frameshift_variant	Exon 16 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251120 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1460698 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726710

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111280

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:13

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

- -

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

- -

May 31, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PP4. -

Nov 21, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS3,PS4_MOD,PM2_SUP -

Dec 20, 2019

Medical Genetics, University of Parma

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.Thr586Valfs*18) 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 present in population databases (rs786202782, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9783703, 16835897, 17311297, 18546366, 25788518). ClinVar contains an entry for this variant (Variation ID: 186215). For these reasons, this variant has been classified as Pathogenic. -

Jun 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000186215). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 17, 2025

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.1756_1759del p.(Thr586ValfsTer18) change deletes four nucleotides to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with Neurofibromatosis type 1 (PMID: 9783703, 17103458, 31766501, 31776437, internal data). In summary, this variant meets criteria to be classified as pathogenic. -

Sep 02, 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

- -

not provided Pathogenic:7

Mar 08, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2_Supporting, PM6 -

Dec 29, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2021

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; Published functional studies demonstrate a damaging effect: variant results in reduced neurofibromin expression and increased RAS activity compared to wild type (Park 1998, Anatasaki 2015); This variant is associated with the following publications: (PMID: 17311297, 9783703, 26514327, 29618358, 28955729, 12807981, 16835897, 18546366, 23906300, 25788518, 28068329, 23758643, 31766501, 31533651, 31476437, 31717729, 32056211, 29625052, 32533764, 31776437) -

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 29, 2017

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. The frequency of this variant in the general population, 0.000004 (1/251120 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with neurofibromatosis 1 (PMID: 31776437 (2020), 32533764 (2020), 34080803 (2021), 34080803 (2022)). A functional study found this variant results in reduced neurofibromin expression compared to wild type (PMID: 25788518 (2015)). Based on the available information, this variant is classified as pathogenic. -

NF1-related disorder Pathogenic:1

Apr 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.1756_1759delACTA variant is predicted to result in a frameshift and premature protein termination (p.Thr586Valfs*18). This variant was reported in individuals with Neurofibromatosis 1 (see for example - Park et al. 1998. PubMed ID: 9783703; Anastasaki et al. 2015. PubMed ID: 25788518; Corsello et al. 2018. PubMed ID: 29618358). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29550493-TTAAC-T) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186215/). Frameshift variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Juvenile myelomonocytic leukemia Pathogenic:1

May 25, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Café-au-lait macules with pulmonary stenosis Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PS2,PS4 -

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

Feb 10, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1756_1759delACTA (p.T586Vfs*18) alteration, located in exon 16 (coding exon 16) of the NF1 gene, consists of a deletion of 4 nucleotides from position 1756 to 1759, causing a translational frameshift with a predicted alternate stop codon after 18 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals diagnosed with NF1, both sporadic and familial (Park, 1998; Fahsold, 2000; Ars, 2003; H&uuml;ffmeier, 2006; Wimmer, 2007; Yap, 2016; Anastasaki, 2017; Melloni, 2019; Yao, 2019; Kang, 2020; Peces, 2020; N Abdel-Aziz, 2021; Riva, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

Neurofibroma Pathogenic:1

Jun 29, 2019

Department of Ophthalmology, Shanghai Ninth people hospital, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 12, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thec.1756_1759delACTApathogenic mutation, located in codingexon16 of theNF1gene, results from a deletion of 4 nucleotides between nucleotide positions 1756 and 1759, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in multiple individuals diagnosed with NF1, both sporadic and familial (Yap P et al. PediatrBlood Cancer. 2015 Oct; [epub ahead of print]; Wimmer K et al. HumMutat. 2007 Jun;28(6):599-612; Ars E et al. J Med Genet. 2003 Jun;40(6):e82; Park VM et al. J Med Genet. 1998 Oct;35(10):813-20). In one functional study, this mutation was reported in a 26 year old female with a clinical diagnosis of NF1, who was found to have 20% neurofibromin expression in fibroblasts (Anastasaki C et al. Hum. Mol. Genet. 2015 Jun; 24(12):3518-28). In addition to the clinical data presented in the literature, sinceframeshiftsare 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
PhyloP100		8.6
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: rs786202782; hg19: chr17-29550493; COSMIC: COSV62199459; COSMIC: COSV62199459;