chr17-31095364-G-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.55G>T(p.Glu19Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000721 in 1,387,822 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 (★★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 7.2e-7 ( 0 hom. )
Consequence
NF1
NM_001042492.3 stop_gained
NM_001042492.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 5.47
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 2921 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-31095364-G-T is Pathogenic according to our data. Variant chr17-31095364-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 186896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095364-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.55G>T | p.Glu19Ter | stop_gained | 1/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.55G>T | p.Glu19Ter | stop_gained | 1/57 | ||
NF1 | NM_001128147.3 | c.55G>T | p.Glu19Ter | stop_gained | 1/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.55G>T | p.Glu19Ter | stop_gained | 1/58 | 1 | NM_001042492.3 | P1 | |
MIR4733HG | ENST00000583377.1 | n.87C>A | non_coding_transcript_exon_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
GnomAD4 exome AF: 7.21e-7 AC: 1AN: 1387822Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 684828
GnomAD4 exome
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1
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1387822
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32
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0
AN XY:
684828
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:4
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 | Institute of Human Genetics, University Hospital Muenster | Aug 31, 2022 | ACMG categories: PVS1,PM2,PP3,PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | This sequence change creates a premature translational stop signal (p.Glu19*) 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 variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 186896). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
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 | Molecular Genetics Lab, CHRU Brest | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 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 at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 10712197, 31768065, 34630515, 26969325) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 11, 2014 | The p.E19* pathogenic mutation (also known as c.55G>T) located in coding exon 1 of the NF1 gene, results from a G to T substitution at nucleotide position 55. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This mutation has been detected in one individual with a clinical diagnosis of neurofibromatosis type 1 (Fahsold R, Am. J. Hum. Genet. 2000 Mar;66(3):790-818). 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
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
0.65, 0.69
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at