rs1060501959

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005732.4(RAD50):​c.1850G>C​(p.Arg617Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RAD50
NM_005732.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12079376).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAD50NM_005732.4 linkuse as main transcriptc.1850G>C p.Arg617Thr missense_variant 12/25 ENST00000378823.8 NP_005723.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAD50ENST00000378823.8 linkuse as main transcriptc.1850G>C p.Arg617Thr missense_variant 12/251 NM_005732.4 ENSP00000368100 P1Q92878-1

Frequencies

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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 30, 2019This sequence change replaces arginine with threonine at codon 617 of the RAD50 protein (p.Arg617Thr). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and threonine. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RAD50-related disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.19
.;.;.;T;T
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.21
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.91
.;.;D;D;D
M_CAP
Benign
0.0077
T
MetaRNN
Benign
0.12
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
.;.;.;L;.
MutationTaster
Benign
0.57
D;N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-1.8
.;.;.;.;N
REVEL
Benign
0.024
Sift
Uncertain
0.0050
.;.;.;.;D
Sift4G
Benign
0.20
.;.;.;T;T
Polyphen
0.0050
.;.;.;B;.
Vest4
0.38
MutPred
0.37
.;.;.;Loss of methylation at K616 (P = 0.0446);.;
MVP
0.43
ClinPred
0.38
T
GERP RS
1.5
Varity_R
0.28
gMVP
0.47

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: rs1060501959; hg19: chr5-131930617; API