5-132637117-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005732.4(RAD50):​c.3392C>A​(p.Ala1131Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

RAD50
NM_005732.4 missense, splice_region

Scores

6
9
2

Clinical Significance

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

Conservation

PhyloP100: 7.57
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAD50NM_005732.4 linkuse as main transcriptc.3392C>A p.Ala1131Glu missense_variant, splice_region_variant 22/25 ENST00000378823.8 NP_005723.2 Q92878-1A5D6Y3
TH2LCRRNR_132124.1 linkuse as main transcriptn.153+1041G>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAD50ENST00000378823.8 linkuse as main transcriptc.3392C>A p.Ala1131Glu missense_variant, splice_region_variant 22/251 NM_005732.4 ENSP00000368100.4 Q92878-1
ENSG00000283782ENST00000640655.2 linkuse as main transcriptc.3095C>A p.Ala1032Glu missense_variant, splice_region_variant 23/265 ENSP00000491596.2 A0A1W2PQ90

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 GeneticsJul 13, 2022The p.A1131E variant (also known as c.3392C>A), located in coding exon 22 of the RAD50 gene, results from a C to A substitution at nucleotide position 3392. The alanine at codon 1131 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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 10, 2020Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with RAD50-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 1131 of the RAD50 protein (p.Ala1131Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.62
.;.;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
.;.;D;D
M_CAP
Benign
0.026
D
MetaRNN
Pathogenic
0.79
D;D;D;D
MetaSVM
Uncertain
0.32
D
MutationAssessor
Pathogenic
3.4
.;.;.;M
PrimateAI
Uncertain
0.66
T
REVEL
Uncertain
0.44
Sift4G
Uncertain
0.012
.;.;.;D
Polyphen
0.98
.;.;.;D
Vest4
0.59
MutPred
0.61
.;.;.;Loss of sheet (P = 0.0817);
MVP
0.79
ClinPred
0.97
D
GERP RS
6.2
Varity_R
0.75
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs1751595703; hg19: chr5-131972809; API