rs1131691085
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.1278G>A(p.Trp426Ter) 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
NF1
NM_001042492.3 stop_gained
NM_001042492.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.53
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 17-31206257-G-A is Pathogenic according to our data. Variant chr17-31206257-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 428962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31206257-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1278G>A | p.Trp426Ter | stop_gained | 12/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.1278G>A | p.Trp426Ter | stop_gained | 12/57 | ||
NF1 | NM_001128147.3 | c.1278G>A | p.Trp426Ter | stop_gained | 12/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.1278G>A | p.Trp426Ter | stop_gained | 12/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2023 | This sequence change creates a premature translational stop signal (p.Trp426*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428962). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 16944272, 26969325). This variant is not present in population databases (gnomAD no frequency). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 25, 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; Not observed in large population cohorts (Lek 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Griffiths 2007, Hutter 2016); This variant is associated with the following publications: (PMID: 26969325, 25525159, 16944272) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2015 | The p.W426* pathogenic mutation (also known as c.1278G>A) located in coding exon 12 of the NF1 gene, results from a G to A substitution at nucleotide position 1278. This changes the amino acid from a tryptophan to a stop codon within coding exon 12. This mutation was seen in an individual who met NIHclinical criteria forNeurofibromatosistype 1 (NF1) (Griffiths S, et al. Fam. Cancer 2007 ; 6(1):21-34).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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
0.97, 0.99
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at