17-31227536-C-A
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.2339C>A(p.Thr780Lys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T780A) 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 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.2339C>A | p.Thr780Lys | missense_variant | 20/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.2339C>A | p.Thr780Lys | missense_variant | 20/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.2339C>A | p.Thr780Lys | missense_variant | 20/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251338Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135842
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 | Genome-Nilou Lab | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | For these reasons, this variant has been classified as Pathogenic. 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: 68316). This missense change has been observed in individual(s) with Neurofibromatosis type 1 (PMID: 1071297, 11735023, 12552569, 15146469, 16944272, 26478990). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs199474746, gnomAD 0.007%). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 780 of the NF1 protein (p.Thr780Lys). - |
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 12, 2017 | The NF1 c.2339C>A; p.Thr780Lys variant (rs199474746) has been reported in multiple unrelated individuals with NF1, and was found de novo in at least one individual (De Luca 2003, De Luca 2004, Esposito 2015, Fahsold 2000, Han 2001). Additionally, two other alterations at this codon (p.Thr780Arg, p.Thr780Pro) have been reported in individuals with NF1 (Griffiths 2007, Laycock-van Spyk 2011). The p.Thr780Lys variant is reported as pathogenic in ClinVar (Variation ID: 68316), and is observed in the general population at a low overall allele frequency of 0.0004% (1/246132 alleles) in the Genome Aggregation Database. The threonine at codon 780 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster, Align GVGD) predict this variant to be damaging to the protein. Taken together, the p.Thr780Lys variant is considered pathogenic. REFERENCES De Luca A et al. NF1 gene analysis based on DHPLC. Hum Mutat. 2003 Feb;21(2):171-2. De Luca A et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum Mutat. 2004 Jun;23(6):629. Esposito T et al. A novel diagnostic method to detect truncated neurofibromin in neurofibromatosis 1. J Neurochem. 2015 Dec;135(6):1123-8. Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Han SS et al. Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1) gene. Hum Genet. 2001 Nov;109(5):487-97. Laycock-van Spyk S et al. Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genomics. 2011 Oct;5(6):623-90. - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 10, 2017 | The p.T780K variant (also known as c.2339C>A), located in coding exon 20 of the NF1 gene, results from a C to A substitution at nucleotide position 2339. The threonine at codon 780 is replaced by lysine, an amino acid with some similar properties. This alteration has been reported multiple times in the literature in individuals who meet NIH neurofibromatosis type 1 diagnostic criteria (Evans DG et al. EBioMedicine, 2016 May;7:212-20; Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; De Luca A et al. Hum. Mutat., 2004 Jun;23:629; Esposito T et al. J. Neurochem., 2015 Dec;135:1123-8). 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