17-31330454-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate
The NM_001042492.3(NF1):c.5768C>T(p.Thr1923Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,624 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1923R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.5768C>T | p.Thr1923Met | missense_variant | 39/58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.3 | c.5705C>T | p.Thr1902Met | missense_variant | 38/57 | NP_000258.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.5768C>T | p.Thr1923Met | missense_variant | 39/58 | 1 | NM_001042492.3 | ENSP00000351015 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152066Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461558Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727094
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74260
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 21, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 187560). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is present in population databases (rs786203824, gnomAD 0.1%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1902 of the NF1 protein (p.Thr1902Met). - |
Neurofibromatosis-Noonan syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Center for Molecular Medicine, Children’s Hospital of Fudan University | Feb 08, 2022 | - - |
Juvenile myelomonocytic leukemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 22, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Absent from cases but present in controls in a breast cancer case-control study (Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 30287823) - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 01, 2016 | The c.5705C>T (p.T1902M) alteration is located in exon 38 (coding exon 38) of the NF1 gene. This alteration results from a C to T substitution at nucleotide position 5705, causing the threonine (T) at amino acid position 1902 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2014 | Thep.T1923Mvariant (also known as c.5768C>T), located in coding exon 39 of theNF1gene, results from a C to T substitution at nucleotide position 5768. The threonine at codon 1923 is replaced by methionine, an amino acid with similar properties. 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.T1923M remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at