rs749322677
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_005732.4(RAD50):c.3193G>A(p.Asp1065Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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. D1065G) has been classified as Uncertain significance.
Frequency
Consequence
NM_005732.4 missense
Scores
Clinical Significance
Conservation
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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.3193G>A | p.Asp1065Asn | missense_variant | 21/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3193G>A | p.Asp1065Asn | missense_variant | 21/25 | 1 | NM_005732.4 | P1 | |
RAD50 | ENST00000533482.5 | c.*2819G>A | 3_prime_UTR_variant, NMD_transcript_variant | 21/25 | 1 | ||||
RAD50 | ENST00000651249.1 | c.31G>A | p.Asp11Asn | missense_variant | 1/6 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250936Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135754
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461162Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726906
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2023 | The p.D1065N variant (also known as c.3193G>A), located in coding exon 21 of the RAD50 gene, results from a G to A substitution at nucleotide position 3193. The aspartic acid at codon 1065 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in a cohort of 81 male breast cancer patients who had multi-gene panel testing (Scarpitta R et al. Breast Cancer Res Treat, 2019 Dec;178:557-564). This amino acid position is poorly 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 | Oct 24, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1065 of the RAD50 protein (p.Asp1065Asn). This variant is present in population databases (rs749322677, 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: 240234). 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%. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 03, 2021 | - - |
Nijmegen breakage syndrome-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 06, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at