5-132608641-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_005732.4(RAD50):c.2745G>C(p.Leu915Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,596,044 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 Uncertain significance (★★).
Frequency
Consequence
NM_005732.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.2745G>C | p.Leu915Phe | missense_variant | Exon 17 of 25 | 1 | NM_005732.4 | ENSP00000368100.4 | ||
ENSG00000283782 | ENST00000640655.2 | c.2448G>C | p.Leu816Phe | missense_variant | Exon 18 of 26 | 5 | ENSP00000491596.2 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151800Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.92e-7 AC: 1AN: 1444244Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 717416
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151800Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74094
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The p.L915F variant (also known as c.2745G>C), located in coding exon 17 of the RAD50 gene, results from a G to C substitution at nucleotide position 2745. The leucine at codon 915 is replaced by phenylalanine, 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 6497 samples (12994 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 457418). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 915 of the RAD50 protein (p.Leu915Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at