17-31235953-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM1PP2BP4_ModerateBS2_Supporting
The NM_001042492.3(NF1):c.3906T>G(p.Asp1302Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251414Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135884
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727220
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2Benign:1
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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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Neurofibromatosis-Noonan syndrome Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided Uncertain:1
This variant is denoted NF1 c.3906T>G at the cDNA level, p.Asp1302Glu (D1302E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a melanoma (Krauthammer 2015). NF1 Asp1302Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the GTPase activating protein domain (Thomas 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Asp1302Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Neurofibromatosis, familial spinal Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Café-au-lait macules with pulmonary stenosis Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
The c.3906T>G (p.D1302E) alteration is located in exon 29 (coding exon 29) of the NF1 gene. This alteration results from a T to G substitution at nucleotide position 3906, causing the aspartic acid (D) at amino acid position 1302 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.D1302E variant (also known as c.3906T>G), located in coding exon 29 of the NF1 gene, results from a T to G substitution at nucleotide position 3906. The aspartic acid at codon 1302 is replaced by glutamic acid, an amino acid with highly 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 0.004% (greater than 110000 alleles tested) in our clinical cohort (includes this individual). Based on protein sequence alignment, this amino acid position is well conserved through sloth, however glutamic acid is the reference amino acid in lower vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.D1302E remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at