chr17-31225224-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS2_Supporting
The NM_001042492.3(NF1):c.1975C>T(p.Arg659Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R659Q) has been classified as Likely benign.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1975C>T | p.Arg659Trp | missense_variant | 17/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.1975C>T | p.Arg659Trp | missense_variant | 17/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.1975C>T | p.Arg659Trp | missense_variant | 17/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251058Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135688
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461460Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727024
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74274
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 659 of the NF1 protein (p.Arg659Trp). This variant is present in population databases (rs757512142, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1, however this individual also carried a second pathogenic variant in the NF1 gene (PMID: 35885913). ClinVar contains an entry for this variant (Variation ID: 184227). 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 not expected to disrupt NF1 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2015 | <span style="background-color:initial">The p.R659W<span style="background-color:initial"> variant (also known as c.1975C>T), located in coding exon 17 of the NF1<span style="background-color:initial"> gene, results from a C to T substitution at nucleotide position 1975. The arginine at codon 659 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species.<span style="background-color:initial">In addition, the in silico prediction for this alteration is inconclusive.<span style="background-color:initial">Since supporting evidence is limited at this time, the clinical significance of p.R659W remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Oct 18, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | NF1: PP2 - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 22, 2021 | The c.1975C>T (p.R659W) alteration is located in exon 17 (coding exon 17) of the NF1 gene. This alteration results from a C to T substitution at nucleotide position 1975, causing the arginine (R) at amino acid position 659 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at