rs745842591
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_005732.4(RAD50):c.581A>T(p.Gln194Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,612,804 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q194H) has been classified as Uncertain significance.
Frequency
Consequence
NM_005732.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.581A>T | p.Gln194Leu | missense_variant | 5/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.581A>T | p.Gln194Leu | missense_variant | 5/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250622Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135508
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1460600Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726680
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 27, 2022 | The p.Q194L variant (also known as c.581A>T), located in coding exon 5 of the RAD50 gene, results from an A to T substitution at nucleotide position 581. The glutamine at codon 194 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well 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 this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 194 of the RAD50 protein (p.Gln194Leu). This variant is present in population databases (rs745842591, gnomAD 0.05%). 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: 185513). 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 RAD50 protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. - |
Nijmegen breakage syndrome-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at