rs863224835
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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):βc.5907_5908delβ(p.Arg1970SerfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000659 in 151,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 29)
Consequence
NF1
NM_001042492.3 frameshift
NM_001042492.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.87
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 17-31334930-CAA-C is Pathogenic according to our data. Variant chr17-31334930-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 216865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334930-CAA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.5907_5908del | p.Arg1970SerfsTer6 | frameshift_variant | 40/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.5844_5845del | p.Arg1949SerfsTer6 | frameshift_variant | 39/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.5907_5908del | p.Arg1970SerfsTer6 | frameshift_variant | 40/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151748Hom.: 0 Cov.: 29
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We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151748Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74076
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: 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: VCV000216865 / PMID: 8069310). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Dr.Nikuei Genetic Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jun 25, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2023 | This sequence change creates a premature translational stop signal (p.Arg1949Serfs*6) 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 I (PMID: 8069310, 16835897). In at least one individual the variant was observed to be de novo. This variant is also known as 5843delAA. ClinVar contains an entry for this variant (Variation ID: 216865). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics, University of Parma | Dec 20, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 12, 2014 | The c.5907_5908delAA variant, located in coding exon 40 of the NF1 gene, results from a deletion of two nucleotides between nucleotide positions 5907 and 5908, causing a translational frameshift with a predicted alternate stop codon. This mutation was confirmed de novo in one individual who was affected with NF1 (<span style="background-color: initial;">Valero MC, et al. Hum. Mol. Genet. 1994 Apr; 3(4):639-41).<span style="background-color: initial;">In addition to the clinical data presented in the literature, since frameshifts 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
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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