NM_001042492.3:c.7348C>T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.7348C>T(p.Arg2450*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R2450R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001042492.3 stop_gained
Scores
Clinical Significance
Conservation
Publications
- neurofibromatosis type 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
- neurofibromatosis-Noonan syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
- Moyamoya diseaseInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NF1 | NM_001042492.3 | MANE Select | c.7348C>T | p.Arg2450* | stop_gained | Exon 50 of 58 | NP_001035957.1 | ||
| NF1 | NM_000267.4 | c.7285C>T | p.Arg2429* | stop_gained | Exon 49 of 57 | NP_000258.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NF1 | ENST00000358273.9 | TSL:1 MANE Select | c.7348C>T | p.Arg2450* | stop_gained | Exon 50 of 58 | ENSP00000351015.4 | ||
| NF1 | ENST00000356175.7 | TSL:1 | c.7285C>T | p.Arg2429* | stop_gained | Exon 49 of 57 | ENSP00000348498.3 | ||
| NF1 | ENST00000579081.6 | TSL:1 | n.*2513C>T | non_coding_transcript_exon | Exon 50 of 58 | ENSP00000462408.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461654Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727118 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:7
The c.7285C>T;p.(Arg2429*) variant creates a premature translational stop signal in the NF1 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 185789; PMID: 10712197; 16944272; 16835897; 25074460) - PS4. This variant is not present in population databases (rs786202457, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
This sequence change creates a premature translational stop signal (p.Arg2429*) 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, 16835897, 16944272, 25074460). ClinVar contains an entry for this variant (Variation ID: 185789). For these reasons, this variant has been classified as Pathogenic.
A known stopgain variant, c.7348C>T in exon 50 of NF1 (Wu-Chou YH, et al., 2018; ClinVar accession ID: VCV000185789.40) was observed in a heterozygous state in the proband. Segregation analysis by Sanger sequencing showed that this variant was present in heterozygous state in the proband, affected mother and brother but absent in the father. This variant is observed in an individual in heterozygous state in gnomAD (v4.1.0) population database and absent in our in-house data of 3748 exomes. The variant c.7348C>T likely introduces a premature termination codon, which may either result in a formation of truncated protein product or cause the transcript to undergo nonsense-medicated mRNA decay
not provided Pathogenic:4
The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16835897, 18484666, 16944272, 14722917, 34427956, 25525159, 22108604, 15060124, 16941471, 10336779, 22155606, 28422438, 10862084, 25074460, 31370276, 10712197, 31730495, 32642735, 30290804, 30877234, 29625052, 27535533, 31776437, 35456261)
The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
not specified Pathogenic:1
The NF1 c.7348C>T; p.Arg2450Ter variant (rs786202457) is reported in the literature in multiple individuals affected with neurofibromatosis type I (Fahsold 2000, Griffiths 2007, Lee 2006). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 185789), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The variant induces an early termination codon, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Arg2450Ter variant is considered to be pathogenic. References: Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000; 66(3):790-818. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Lee MJ et al. Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Hum Mutat. 2006 Aug;27(8):832.
Subcutaneous neurofibroma;C1860334:Lisch nodules Pathogenic:1
Malignant tumor of urinary bladder Pathogenic:1
NF1-related disorder Pathogenic:1
The NF1 c.7348C>T variant is predicted to result in premature protein termination (p.Arg2450*). This variant is alternatively referred to as c.7285C>T (p.Arg2429*) using the primary transcript NM_000267. This variant has been reported in multiple individuals with neurofibromatosis type I (Fahsold et al. 2000. PubMed ID: 10712197; Lee et al. 2006. PubMed ID: 16835897; Griffiths et al. 2007. PubMed ID: 16944272). At PreventionGenetics, we previously identified this variant in other affected patients. To our knowledge, this variant has not been reported in in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185789/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Juvenile myelomonocytic leukemia Pathogenic:1
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.R2450* pathogenic mutation (also known as c.7348C>T) located in coding exon 50 of the NF1 gene, results from a C to T substitution at nucleotide position 7348. This changes the amino acid from an arginine to a stop codon within coding exon 50. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at