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rs786201874

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001042492.3(NF1):c.499_502del(p.Cys167GlnfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 612,326 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: 0.0000016 ( 0 hom. )

Consequence

NF1
NM_001042492.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 8.72
Variant links:
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]

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ACMG classification

Classification made for transcript

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 17-31169905-CTGTT-C is Pathogenic according to our data. Variant chr17-31169905-CTGTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 185021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31169905-CTGTT-C is described in Lovd as [Pathogenic]. Variant chr17-31169905-CTGTT-C is described in Lovd as [Likely_pathogenic]. Variant chr17-31169905-CTGTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NF1NM_001042492.3 linkuse as main transcriptc.499_502del p.Cys167GlnfsTer10 frameshift_variant 5/58 ENST00000358273.9
NF1NM_000267.3 linkuse as main transcriptc.499_502del p.Cys167GlnfsTer10 frameshift_variant 5/57
NF1NM_001128147.3 linkuse as main transcriptc.499_502del p.Cys167GlnfsTer10 frameshift_variant 5/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NF1ENST00000358273.9 linkuse as main transcriptc.499_502del p.Cys167GlnfsTer10 frameshift_variant 5/581 NM_001042492.3 P1P21359-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251028
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135724
show subpopulations
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 SAS 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:
0.00000163
AC:
1
AN:
612326
Hom.:
0
AF XY:
0.00000299
AC XY:
1
AN XY:
334644
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000231
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:21
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:11
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenOct 26, 2020- -
Pathogenic, criteria provided, single submitterclinical testing3billionMay 22, 2022The 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. -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 13, 2024This 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. -
Pathogenic, criteria provided, single submitterclinical testingMedical Genetics, University of ParmaDec 20, 2019- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaDec 05, 2019This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 27, 2022- -
Pathogenic, flagged submissionclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalNov 11, 2020- -
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalJul 15, 2014- -
Pathogenic, no assertion criteria providedclinical testingClinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)Apr 01, 2023- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
not provided Pathogenic:7
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 11, 2019- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJan 08, 2013This 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. -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJan 26, 2021PVS1, PM6_Strong, PM2 -
Pathogenic, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalDec 17, 2022- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 15, 2022Frameshift 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) -
Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis Pathogenic:1
Pathogenic, criteria provided, single submitterresearchThe Laboratory of Genetics and Metabolism, Hunan Children’s HospitalNov 10, 2018- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2014- -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 15, 2021The 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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786201874; hg19: chr17-29496923; API