rs77642085

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005732.4(RAD50):​c.3080G>T​(p.Arg1027Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

RAD50
NM_005732.4 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.96
Variant links:
Genes affected
RAD50 (HGNC:9816): (RAD50 double strand break repair protein) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAD50NM_005732.4 linkuse as main transcriptc.3080G>T p.Arg1027Ile missense_variant 20/25 ENST00000378823.8 NP_005723.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAD50ENST00000378823.8 linkuse as main transcriptc.3080G>T p.Arg1027Ile missense_variant 20/251 NM_005732.4 ENSP00000368100 P1Q92878-1
RAD50ENST00000533482.5 linkuse as main transcriptc.*2706G>T 3_prime_UTR_variant, NMD_transcript_variant 20/251 ENSP00000431225
RAD50ENST00000651723.1 linkuse as main transcript downstream_gene_variant ENSP00000498237

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 01, 2023The p.R1027I variant (also known as c.3080G>T), located in coding exon 20 of the RAD50 gene, results from a G to T substitution at nucleotide position 3080. The arginine at codon 1027 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 14, 2023This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 1027 of the RAD50 protein (p.Arg1027Ile). This variant is not present in population databases (gnomAD no frequency). 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: 187019). 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. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Uncertain
0.036
T
BayesDel_noAF
Benign
-0.19
CADD
Pathogenic
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.12
.;.;.;T
Eigen
Benign
0.092
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
.;.;D;D
M_CAP
Benign
0.036
D
MetaRNN
Uncertain
0.49
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.1
.;.;.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Uncertain
-4.3
.;.;.;D
REVEL
Benign
0.18
Sift
Benign
0.15
.;.;.;T
Sift4G
Benign
0.069
.;.;.;T
Polyphen
0.15
.;.;.;B
Vest4
0.82
MutPred
0.46
.;.;.;Loss of MoRF binding (P = 0.0837);
MVP
0.55
ClinPred
0.98
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.31
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs77642085; hg19: chr5-131951738; API