5-132642282-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_005732.4(RAD50):c.3857T>C(p.Phe1286Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,728 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1286C) has been classified 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.3857T>C | p.Phe1286Ser | missense_variant | 25/25 | ENST00000378823.8 | |
TH2LCRR | NR_132125.1 | n.105A>G | splice_region_variant, non_coding_transcript_exon_variant | 2/3 | |||
TH2LCRR | NR_132126.1 | n.175-4017A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3857T>C | p.Phe1286Ser | missense_variant | 25/25 | 1 | NM_005732.4 | P1 | |
TH2LCRR | ENST00000435042.1 | n.95A>G | splice_region_variant, non_coding_transcript_exon_variant | 2/4 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461728Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727190
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 27, 2022 | The p.F1286S variant (also known as c.3857T>C), located in coding exon 25 of the RAD50 gene, results from a T to C substitution at nucleotide position 3857. The phenylalanine at codon 1286 is replaced by serine, an amino acid with highly dissimilar properties. 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 this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 10, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1286 of the RAD50 protein (p.Phe1286Ser). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 140919). 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 expected to disrupt RAD50 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at