rs760550772
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_ModerateBP6BS2_Supporting
The NM_001042492.3(NF1):c.8490C>A(p.Phe2830Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.8490C>A | p.Phe2830Leu | missense_variant | 58/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.8427C>A | p.Phe2809Leu | missense_variant | 57/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.8490C>A | p.Phe2830Leu | missense_variant | 58/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251322Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135824
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461778Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 727186
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 29, 2015 | The p.F2830L variant (also known as c.8490C>A), located in coding exon 58 of the NF1 gene, results from a C to A substitution at nucleotide position 8490. The phenylalanine at codon 2830 is replaced by leucine, 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 0.005% (greater than 110000 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.F2830L remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 27, 2021 | - - |
Neurofibromatosis, type 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2018 | This variant is denoted NF1 c.8427C>A at the cDNA level, p.Phe2809Leu (F2809L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Phe2809Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Luo 2014). 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 Phe2809Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at