rs786201768
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BS2_Supporting
The NM_001042492.3(NF1):c.2042G>A(p.Arg681Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R681L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.2042G>A | p.Arg681Gln | missense_variant | 18/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.2042G>A | p.Arg681Gln | missense_variant | 18/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.2042G>A | p.Arg681Gln | missense_variant | 18/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250710Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135486
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461546Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3AN XY: 727078
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2023 | 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 184891). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is present in population databases (rs786201768, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 681 of the NF1 protein (p.Arg681Gln). - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2021 | The c.2042G>A (p.R681Q) alteration is located in exon 18 (coding exon 18) of the NF1 gene. This alteration results from a G to A substitution at nucleotide position 2042, causing the arginine (R) at amino acid position 681 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2014 | Thep.R681Q variant (also known as c.2042G>A), located in coding exon 18 of theNF1 gene, results from a G to A substitution at nucleotide position 2042. The arginine at codon 681 is replaced by glutamine, an amino acid with highly similar 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. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 5000 alleles tested) in our clinical cohort (includes this individual). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFTin silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.R681Q remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at