17-31338092-C-T

Variant summary

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

The NM_001042492.3(NF1):​c.6772C>T​(p.Arg2258*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. )

Consequence

NF1
NM_001042492.3 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:25

Conservation

PhyloP100: 1.54
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 17-31338092-C-T is Pathogenic according to our data. Variant chr17-31338092-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 230389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31338092-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NF1NM_001042492.3 linkc.6772C>T p.Arg2258* stop_gained 45/58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.3 linkc.6709C>T p.Arg2237* stop_gained 44/57 NP_000258.1 P21359-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkc.6772C>T p.Arg2258* stop_gained 45/581 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461654
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727148
show subpopulations
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:25
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:13
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, National Health Laboratory Service/University of the Witwatersrand-- -
Pathogenic, criteria provided, single submitterresearchDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDec 15, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenOct 26, 2020- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based 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 for this gene and is associated with NF1-related disorders. (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 or less severly affected than a heterozygote 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 - Variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted 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. The variant has previously been reported as pathogenic in multiple patients with NF1, including some cases with confirmed de novo inheritance (ClinVar, PMID: 10712197, 31776437). (SP) 1208 - Inheritance information for this variant is not currently available. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterApr 04, 2024- -
Pathogenic, no assertion criteria providedresearchKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
Pathogenic, criteria provided, single submitterclinical testingSuma Genomics-- -
Pathogenic, criteria provided, single submitterclinical testingMedical Genetics, University of ParmaDec 20, 2019- -
Pathogenic, criteria provided, single submitterclinical testing3billionMay 22, 2022The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): 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: VCV000230389 / PMID: 10712197). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 17, 2023This sequence change creates a premature translational stop signal (p.Arg2237*) 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: 10712197, 10862084, 12552569, 16479075, 23913538, 26962827). This variant is also known as R2258X. ClinVar contains an entry for this variant (Variation ID: 230389). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:6
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2021- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 02, 2022Nonsense 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: 26962827, 10712197, 16479075, 25525159, 12112660, 27498913, 27617404, 12552569, 23913538, 10862084, 34308366, 31730495, 31717729, 31533797, 31370276, 32283115, 31776437) -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoOct 29, 2024The NF1 c.6709C>T (p.Arg2237*) variant causes the premature termination of NF1 protein synthesis. This variant has been reported in the published literature in individuals with neurofibromatosis 1 (NF1) (PMID: 10712197 (2000), 10862084 (2000), 12552569 (2003), 23913538 (2013), 26962827 (2016), 31370276 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis Pathogenic:1
Pathogenic, criteria provided, single submitterresearchThe Laboratory of Genetics and Metabolism, Hunan Children’s HospitalNov 10, 2018- -
NF1-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 28, 2024The NF1 c.6772C>T variant is predicted to result in premature protein termination (p.Arg2258*). This variant has been reported in individuals with neurofibromatosis type 1 (referred to as R2237X in Fahsold et al. 2000. PubMed ID: 10712197; Zhu et al. 2016. PubMed ID: 26962827). At PreventionGenetics, this variant has been identified in other affected patients. To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/230389/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingJuno Genomics, Hangzhou Juno Genomics, Inc-PM2_Supporting+PVS1+PM6_Supporting+PS4_Moderate+PP1_Strong+PP4 -
Café-au-lait macules with pulmonary stenosis Pathogenic:1
Pathogenic, criteria provided, single submitterresearchAl Jalila Children’s Genomics Center, Al Jalila Childrens Speciality HospitalOct 04, 2024PVS1,PS2,PM2 -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 04, 2024The c.6709C>T (p.R2237*) alteration, located in exon 44 (coding exon 44) of the NF1 gene, consists of a C to T substitution at nucleotide position 6709. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 2237. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been described in multiple individuals meeting NIH diagnostic criteria for neurofibromatosis type 1 (NF1) (Fahsold, 2000; Xu, 2014; Zhu, 2016). This alteration is a recurring mutation due to its location in a CpG dinucleotide. Of note, this mutation is also designated as c.67772C>T and p.R2258* in published literature. Based on the available evidence, this alteration is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 08, 2015​Thep.R2258*pathogenic mutation (also known as c.6772C>T, p.R2237X, and c.6709C>T)<span style="font-size:12.7272720336914px">located in coding exon 45 of theNF1<span style="font-size:12.7272720336914px">gene, results from a C to T substitution at nucleotide position 6772. This changes the amino acid from an arginine to a stop codon within coding exon 45. This alteration was first described in three unrelated individuals who all met NIH diagnostic criteria forneurofibromatosis type 1 (NF1) (Fahsold R et al.Am J Hum Genet.2000;66(3):790-818). This alteration is a recurring mutation due to being located in a CpG dinucleotide. In addition to the clinical data presented in the literature, since premature stop codons 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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.62
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.94
D
Vest4
0.93
GERP RS
4.5

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.35
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.35
Position offset: 47

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: rs876658541; hg19: chr17-29665110; COSMIC: COSV62192184; COSMIC: COSV62192184; API