rs1060500342
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001042492.3(NF1):c.6685T>C(p.Trp2229Arg) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. 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. W2229C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.6685T>C | p.Trp2229Arg | missense_variant | 44/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.6622T>C | p.Trp2208Arg | missense_variant | 43/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.6685T>C | p.Trp2229Arg | missense_variant | 44/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2018 | This sequence change replaces tryptophan with arginine at codon 2208 of the NF1 protein (p.Trp2208Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. 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. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with neurofibromatosis type 1 (NF1) (external communication). It has also been observed to segregate with clinical features of NF1 in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 404554). This variant is not present in population databases (ExAC no frequency). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 21, 2023 | The p.W2208R variant (also known as c.6622T>C), located in coding exon 43 of the NF1 gene, results from a T to C substitution at nucleotide position 6622. The tryptophan at codon 2208 is replaced by arginine, an amino acid with dissimilar properties. The variant was detected in multiple individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 and co-segregated with disease in one family, and has been observed in additional individuals with a personal and/or family history that is consistent with NF1-related disease (Ambry internal data). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2020 | The p.W2229R variant (also known as c.6685T>C), located in coding exon 43 of the NF1 gene, results from a T to C substitution at nucleotide position 6622. The tryptophan at codon 2208 is replaced by arginine, an amino acid with dissimilar properties. The variant was detected in multiple individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 and co-segregated with disease in one family (Ambry internal data). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at