rs1060500363
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.79C>T(p.Gln27Ter) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q27Q) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
NF1
NM_001042492.3 stop_gained
NM_001042492.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 7.43
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]
Genome browser will be placed here
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 2908 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-31156001-C-T is Pathogenic according to our data. Variant chr17-31156001-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 404581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.79C>T | p.Gln27Ter | stop_gained | 2/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.79C>T | p.Gln27Ter | stop_gained | 2/57 | ||
NF1 | NM_001128147.3 | c.79C>T | p.Gln27Ter | stop_gained | 2/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.79C>T | p.Gln27Ter | stop_gained | 2/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics, University of Parma | Feb 02, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 29, 2023 | This premature translational stop signal has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 29685074). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln27*) 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). ClinVar contains an entry for this variant (Variation ID: 404581). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2017 | - - |
Juvenile myelomonocytic leukemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 04, 2022 | - - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2021 | The p.Q27* pathogenic mutation (also known as c.79C>T), located in coding exon 2 of the NF1 gene, results from a C to T substitution at nucleotide position 79. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This variant has been observed in individuals with clinical features of neurofibromatosis type 1(Rosset C et al. Expert Rev Mol Diagn, 2018 06;18:577-586) (Demir Gündoan B et al. Turk J Med Sci, 2021 Aug). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
0.93, 0.97
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