rs587782637
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PP5
The NM_005732.4(RAD50):c.3443G>A(p.Arg1148His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,611,372 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1148C) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.3443G>A | p.Arg1148His | missense_variant | 22/25 | ENST00000378823.8 | |
TH2LCRR | NR_132124.1 | n.153+990C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3443G>A | p.Arg1148His | missense_variant | 22/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151908Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251442Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135894
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1459464Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 726058
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151908Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74174
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 29, 2022 | The p.R1148H variant (also known as c.3443G>A), located in coding exon 22 of the RAD50 gene, results from a G to A substitution at nucleotide position 3443. The arginine at codon 1148 is replaced by histidine, an amino acid with highly similar 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 | Nov 13, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1148 of the RAD50 protein (p.Arg1148His). This variant is present in population databases (rs587782637, gnomAD 0.003%). 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: 142677). 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 with a positive predictive value of 80%. 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. - |
Ovarian cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at