rs786201874

Variant names:

• chr17-31169905-CTGTT-C
• rs786201874
• NM_001042492.3:c.499_502delTGTT

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.499_502delTGTT​(p.Cys167GlnfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:25
• Conservation: PhyloP100: 8.72
• Publications: 15 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 17-31169905-CTGTT-C is Pathogenic according to our data. Variant chr17-31169905-CTGTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 185021.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.499_502delTGTT	p.Cys167GlnfsTer10	frameshift_variant	Exon 5 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.499_502delTGTT	p.Cys167GlnfsTer10	frameshift_variant	Exon 5 of 57		NP_000258.1
NF1	NM_001128147.3	c.499_502delTGTT	p.Cys167GlnfsTer10	frameshift_variant	Exon 5 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.499_502delTGTT	p.Cys167GlnfsTer10	frameshift_variant	Exon 5 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251028 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442702 Hom.: 0 AF XY: 0.00000139 AC XY: 1 AN XY: 718206

African (AFR) AF: 0.00 AC: 0 AN: 32748

American (AMR) AF: 0.0000226 AC: 1 AN: 44196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25386

East Asian (EAS) AF: 0.00 AC: 0 AN: 38112

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100018

Other (OTH) AF: 0.00 AC: 0 AN: 59034

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:13

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: VCV000185021 / PMID: 10543400). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 11, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2019

Medical Genetics, University of Parma

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

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM2_Supporting+PS4+PP4 -

Dec 24, 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.Cys167Glnfs*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 present in population databases (rs786201874, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 10543400, 24294391). This variant is also known as 495delTGTT. ClinVar contains an entry for this variant (Variation ID: 185021). For these reasons, this variant has been classified as Pathogenic. -

Dec 05, 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. -

Jul 15, 2014

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

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

Jul 31, 2024

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys167Glnfs*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 present in population databases (rs786201874, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (NF1) . This variant is associated with the following publications: (PMID: 18546366, 17726231, 17311297, 31533797, 24294391, 22155606, 12807981, 18041031, 10543400, 24676424, 20844836, 23913538, 30293248, 30530636, 28191890, 16835897, 24789688, 27838393, 28152038, 31730495, 30098238, 31370276, 34246755, 31066482).. This variant is also known as 495delTGTT. ClinVar contains an entry for this variant (Variation ID: 185021). For these reasons, this variant has been classified as Pathogenic. -

Jul 27, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:8

Sep 05, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2_moderate, PM6, PVS1 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 26, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM6_Strong, PM2 -

Jun 11, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2024

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP5;PP4;PVS1 -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 15, 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; Also known as c.495delTGTT; This variant is associated with the following publications: (PMID: 18546366, 17726231, 17311297, 31533797, 24294391, 22155606, 12807981, 18041031, 10543400, 24676424, 20844836, 23913538, 30293248, 30530636, 28191890, 16835897, 24789688, 27838393, 28152038, 31730495, 30098238, 31370276, 34246755, 31066482) -

Jan 08, 2013

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. In the published literature, the variant has been reported in individuals/families with neurofibromatosis 1 (NF1) or with clinical suspicion of NF1 (PMID: 34427956 (2022), 30530636 (2019), 27838393 (2017), 23913538 (2013), 17311297 (2007), 12807981 (2003), 10726756 (2000), 10543400 (1999)). Based on the available information, this variant is classified as pathogenic. -

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

- -

Inborn genetic diseases Pathogenic:1

Jun 06, 2014

Ambry 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, PS4, PM2 -

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

Sep 15, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.499_502delTGTT variant, located in coding exon 5 of the NF1 gene, results from a deletion of 4 nucleotides at nucleotide positions 499 to 502, causing a translational frameshift with a predicted alternate stop codon (p.C167Qfs*10). This mutation has been observed in multiple patients with sporadic or familial NF1 (Osborn MJ and Upadhyaya M. Hum. Genet. 1999 Oct;105:327-32; Toliat MR et al. Electrophoresis. 2000 Feb;21:541-4; Ars E et al. J. Med. Genet. 2003 Jun;40:e82; Schaefer IM et al. Int J Clin Exp Pathol, 2013 Nov;6:3003-8; Uusitalo E et al. Acta Derm. Venereol., 2014 Nov;94:663-6; Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60; Giugliano T et al. Genes (Basel) 2019 07;10(8)). Of note, this mutation is also designated as c.495delTGTT and c.495_498del in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
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: rs786201874; hg19: chr17-29496923; COSMIC: COSV62217662;