rs576687606
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP6
The NM_001042492.3(NF1):āc.3940T>Cā(p.Trp1314Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. W1314L) 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.3940T>C | p.Trp1314Arg | missense_variant | 29/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.3940T>C | p.Trp1314Arg | missense_variant | 29/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.3940T>C | p.Trp1314Arg | missense_variant | 29/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251400Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135874
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461814Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727206
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152254Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74456
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1314 of the NF1 protein (p.Trp1314Arg). This variant is present in population databases (rs576687606, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 577999). 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 not expected to disrupt NF1 protein function with a negative predictive value of 95%. 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. - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 18, 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