rs1060500367
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.2534G>A(p.Cys845Tyr) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C845R) has been classified as Pathogenic.
Frequency
Consequence
NM_001042492.3 missense
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.2534G>A | p.Cys845Tyr | missense_variant | 21/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.2534G>A | p.Cys845Tyr | missense_variant | 21/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.2534G>A | p.Cys845Tyr | missense_variant | 21/58 | 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:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 22, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys845 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 404587). This missense change has been observed in individual(s) with neurofibromatosis type 1 (NF1) and features of NF1 (PMID: 23656349, 29290338; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 845 of the NF1 protein (p.Cys845Tyr). - |
Pathogenic, criteria provided, single submitter | clinical testing | Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center | Feb 26, 2021 | The c.2534G>A variant in the NF1 gene is a heterozygous missense variant, which results in the substitution of the conserved cysteine residue at the 845 position to tyrosine (p.Cys845Tyr). This variant has been observed in the heterozygous state in multiple individuals with clinical features of Neurofibromatosis, type 1 (PMIDs: 29290338, 23656349, and 30014477) and has been reported in ClinVar as Pathogenic (Variation ID: 404587; Last accessed: 2/25/2021). It falls in the cysteine-serine-rich domain of the protein, and variants in codons 844-848 have been shown to be associated with a more severe presentation of neurofibromatosis type 1. Additionally, variants in these codons were identified in ~0.8% of unrelated variant-positive individuals in a large cohort of individuals with NF1, suggesting a mutational hotspot (PMID: 29290338). This variant is not observed in the Genome Aggregation Database (gnomAD), indicating it is not a common benign variant in the populations represented in this database. In addition, a different missense variant in the same position, c.2533T>C, p.Cys845Arg has also been reported in the ClinVar database as Pathogenic (Variation ID: 404431; Last accessed: 2/25/2021). - |
Pathogenic, criteria provided, single submitter | clinical testing | UAB Medical Genomics Laboratory, UAB Medicine | Jun 05, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at