rs1060500360
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_Very_Strong
The NM_001042492.3(NF1):c.248A>C(p.Gln83Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q83Q) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
NF1
NM_001042492.3 missense
NM_001042492.3 missense
Scores
7
5
7
Clinical Significance
Conservation
PhyloP100: 8.59
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 13 ACMG points.
PM1
In a helix (size 22) in uniprot entity NF1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001042492.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
PP5
Variant 17-31159053-A-C is Pathogenic according to our data. Variant chr17-31159053-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 641956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31159053-A-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.248A>C | p.Gln83Pro | missense_variant | 3/58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.3 | c.248A>C | p.Gln83Pro | missense_variant | 3/57 | NP_000258.1 | ||
NF1 | NM_001128147.3 | c.248A>C | p.Gln83Pro | missense_variant | 3/15 | NP_001121619.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.248A>C | p.Gln83Pro | missense_variant | 3/58 | 1 | NM_001042492.3 | ENSP00000351015.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely 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 | Labcorp Genetics (formerly Invitae), Labcorp | May 25, 2023 | This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 23913538). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 641956). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 83 of the NF1 protein (p.Gln83Pro). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2022 | Reported to segregate with disease in individuals with neurofibromatosis type 1 from a single family in published literature, however, family-specific clinical information and pedigree were not provided (Sabbagh et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34418705, 23913538) - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2019 | The p.Q83P variant (also known as c.248A>C), located in coding exon 3 of the NF1 gene, results from an A to C substitution at nucleotide position 248. The glutamine at codon 83 is replaced by proline, an amino acid with similar properties. This alteration was detected in an individual meeting NIH diagnostic criteria for Neurofibromatosis type 1 (NF1) (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
DEOGEN2
Uncertain
.;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
M;M;M;M
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;N;D
REVEL
Uncertain
Sift
Benign
.;T;T;D
Sift4G
Benign
.;T;T;T
Polyphen
D;D;D;.
Vest4
0.95, 0.94
MutPred
Loss of helix (P = 0.0076);Loss of helix (P = 0.0076);Loss of helix (P = 0.0076);Loss of helix (P = 0.0076);
MVP
0.75
MPC
1.7
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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