17-31327653-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PP2PP3_ModerateBS2_Supporting
The NM_001042492.3(NF1):c.5423C>T(p.Thr1808Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,012 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. T1808A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152118Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251386Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135854
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727248
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152118Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74290
ClinVar
Submissions by phenotype
not provided Uncertain:3
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Momozawa 2018); This variant is associated with the following publications: (PMID: 16835897, 30287823, 21089070, 30104198) -
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Neurofibromatosis, type 1 Uncertain:2Benign:1
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Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Uncertain:1
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Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
The c.5360C>T (p.T1787M) alteration is located in exon 37 (coding exon 37) of the NF1 gene. This alteration results from a C to T substitution at nucleotide position 5360, causing the threonine (T) at amino acid position 1787 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
Thep.T1808Mvariant (also known as c.5423C>T) located in coding exon 38 of theNF1gene, results from a C to T substitution at nucleotide position 5423. The threonine at codon 1808 is replaced by methionine, an amino acid with similar properties. This alteration was first reported in a 33 year old Chinese male suspicious for neurofibromatosis type 1 (Lee MJ, Hum. Mutat. 2006 Aug; 27(8):832). 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.T1808M remains unclear. This alteration has also been designated as p.T1787M(c.5360C>T) in published literature. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at