17-31357308-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.7909C>T(p.Arg2637Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,702 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
NF1
NM_001042492.3 stop_gained
NM_001042492.3 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.60
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 17-31357308-C-T is Pathogenic according to our data. Variant chr17-31357308-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 184261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31357308-C-T is described in Lovd as [Pathogenic]. Variant chr17-31357308-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NF1 | NM_001042492.3 | c.7909C>T | p.Arg2637Ter | stop_gained | 54/58 | ENST00000358273.9 | NP_001035957.1 | |
| NF1 | NM_000267.3 | c.7846C>T | p.Arg2616Ter | stop_gained | 53/57 | NP_000258.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NF1 | ENST00000358273.9 | c.7909C>T | p.Arg2637Ter | stop_gained | 54/58 | 1 | NM_001042492.3 | ENSP00000351015 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461702Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727142
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GnomAD4 genome
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32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Sep 22, 2022 | c.7909C>T in NF1 has been reported in multiple unrelated individuals with Neurofibromatosis type 1 including as a de novo occurrence. It has also been reported in a parent and child with Neurofibromatosis-Noonan syndrome. The variant (rs786201367) is absent from a large population dataset and has been reported in ClinVar (Variation ID 184261). This nonsense variant results in a premature stop codon in exon 54 of 58, likely leading to nonsense-mediated decay and lack of protein production. We consider c.7909C>T in NF1 to be pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Aug 28, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Apr 30, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 26, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jul 21, 2021 | PVS1, PS4, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 06, 2018 | The NF1 c.7846C>T (p.Arg2616Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg2616Ter variant has been reported in at least nine studies and is found in at least 25 probands in a heterozygous state (Upadhyaya et al. 1995; Osborn et al. 1999; Fahsold et al. 2000; Wang et al. 2003; De Luca et al. 2004; Shirinzi et al. 2006; Stevenson et al. 2006; Messiaen and Wimmer 2008; Vuralli et al. 2016). Two probands were related and had clinical features of NF1 and neurofibromatosis-Noonan syndrome. The p.Arg2616Ter variant was absent from 152 controls (De Luca et al. 2004; Shirinzi et al. 2006) and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or Genome Aggregation Database. Due to the potential impact of stop-gained variants and the evidence in the literature, the p.Arg2616Ter variant is classified as pathogenic for NF1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg2616*) 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: 8544190, 10712197, 15146469, 25074460, 25326637, 27838393). ClinVar contains an entry for this variant (Variation ID: 184261). RNA analysis provides insufficient evidence to determine the effect of this variant on NF1 splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 06, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 03, 2023 | Variant summary: NF1 c.7846C>T (p.Arg2616X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 251314 control chromosomes (gnomAD). c.7846C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (e.g. Upadhyaya_1995, De Luca_2004, Sabbagh_2013, Zhu_2019). These data indicate that the variant is very likely to be associated with disease. Fifteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics, University of Parma | Dec 20, 2019 | - - |
Neurofibromatosis-Noonan syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | 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 (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000184261, PMID:8544190, 3billion dataset).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 09, 2024 | Criteria applied: PVS1,PS4,PM2_SUP - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2021 | Nonsense 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; This variant is associated with the following publications: (PMID: 25525159, 25074460, 10543400, 29872864, 31551924, 26758488, 26962827, 8544190, 10712197, 15146469, 27838393, 25326637, 29158289, 28152038, 16773574, 16544997, 30530636, 12522551, 31776437, 30612635, 31730495, 31533797) - |
Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital | Nov 10, 2018 | - - |
NF1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 18, 2023 | The NF1 c.7909C>T variant is predicted to result in premature protein termination (p.Arg2637*). This variant, also referred to as c.7846C>T (p.Arg2616*), has been reported in multiple individuals with neurofibromatosis type 1 (Upadhyaya. 1995. PubMed ID: 8544190; Vuralli. 2016. PubMed ID: 26758488; Zhu. 2016. PubMed ID: 26962827; Table S3 - LaDuca. 2017. PubMed ID: 28152038; Gieldon. 2018. PubMed ID: 29158289). Loss-of-function variants in NF1 are known to be pathogenic (Fahsold. 2000 et al. PubMed ID: 10712197). To our knowledge, 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/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184261/). 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 submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Juvenile myelomonocytic leukemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 23, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2020 | The p.R2637* pathogenic mutation (also known as c.7909C>T), located in coding exon 54 of the NF1 gene, results from a C to T substitution at nucleotide position 7909. This changes the amino acid from an arginine to a stop codon within coding exon 54. This pathogenic mutation has been described in an individual who presented with classic cutaneous involvement and plexiform neurofibromas (Upadhyaya M et al. J. Med. Genet. 1995; 32:706-10). In addition, this alteration was also found in an affected patient presenting with Cafe-au-Lait spots, axillary freckling, nodular neurofibromas, lisch nodules and scoliosis (De Luca A et al. Hum. Mutat. 2004; 23:629). 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). This mutation is also known as p.R2616* and c.7846C>T in the literature. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at