rs1060500308
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.3763C>T(p.Gln1255Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Q1255Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001042492.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.3763C>T | p.Gln1255Ter | stop_gained | 28/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.3763C>T | p.Gln1255Ter | stop_gained | 28/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.3763C>T | p.Gln1255Ter | stop_gained | 28/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2016 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in NF1 are known to be pathogenic. This particular variant has been reported in the literature in an individual affected with neurofibromatosis type 1 (PMID: 23913538). This sequence change creates a premature translational stop signal at codon 1255 (p.Gln1255*) of the NF1 gene. It is expected to result in an absent or disrupted protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2017 | This variant is denoted NF1 c.3763C>T at the cDNA level and p.Gln1255Ter (Q1255X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with neurofibromatosis (Sabbagh 2013) and is considered pathogenic. - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2021 | The p.Q1255* pathogenic mutation (also known as c.3763C>T), located in coding exon 28 of the NF1 gene, results from a C to T substitution at nucleotide position 3763. This changes the amino acid from a glutamine to a stop codon within coding exon 28. This mutation has been detected in individuals reported to have neurofibromatosis type 1 (Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Kang E et al. J Hum Genet, 2020 Jan;65:79-89). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at