17-31230373-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5
The NM_001042492.3(NF1):c.3104T>C(p.Met1035Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1035K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.3104T>C | p.Met1035Thr | missense_variant | 23/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.3104T>C | p.Met1035Thr | missense_variant | 23/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.3104T>C | p.Met1035Thr | missense_variant | 23/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461120Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726858
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1035 of the NF1 protein (p.Met1035Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a clinical diagnosis or suspicion of neurofibromatosis type 1 (PMID: 24789688; Invitae). ClinVar contains an entry for this variant (Variation ID: 431618). 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. This variant disrupts the p.Met1035 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. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics, University of Parma | Aug 17, 2022 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2023 | Observed in an individual with a diagnosis or clinical suspicion of neurofibromatosis type 1 (Xu et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Martorana2022[CaseReport], 25486365, 2121369, 24789688, 26582918, 24077912, 31370276, 34080803) - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 27, 2016 | The p.M1035T variant (also known as c.3104T>C), located in coding exon 23 of the NF1 gene, results from a T to C substitution at nucleotide position 3104. The methionine at codon 1035 is replaced by threonine, an amino acid with similar properties. This variant was listed as novel in a cohort that either met clinical criteria or were suspected to have neurofibromatosis type 1; however, no specific clinical information was provided about the patient with this variant (Xu W, Int. J. Mol. Med. 2014 Jul; 34(1):53-60). 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. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at