rs1555614462
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.2990G>A(p.Arg997Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R997G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.2990G>A | p.Arg997Lys | missense_variant, splice_region_variant | 22/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.2990G>A | p.Arg997Lys | missense_variant, splice_region_variant | 22/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.2990G>A | p.Arg997Lys | missense_variant, splice_region_variant | 22/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 23, 2018 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this nucleotide change can result in skipping of exon 22. Exon 22 is also known as exon 17 in the literature (PMID: 23913538). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with neurofibromatosis type 1 (PMID: 23913538, 29673180, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 997 of the NF1 protein (p.Arg997Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 22 of the NF1 coding sequence, which is part of the consensus splice site for this exon. - |
Juvenile myelomonocytic leukemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 20, 2023 | - - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2019 | The c.2990G>A pathogenic mutation (also known as p.R997K), located in coding exon 22 of the NF1 gene, results from a G to A substitution at nucleotide position 2990. The amino acid change results in arginine to lysine at codon 997, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 22, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in a French NF1 cohort and is reported to result in exon skipping (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, a slight weakening in the native splice donor site efficiency and a weakening in the native splice donor site efficiency are predicted, respectively. Based on the available evidence, this variant is classified as a pathogenic mutation. . - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at