rs1554100862

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005732.4(RAD50):ā€‹c.3437T>Cā€‹(p.Ile1146Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,098 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

RAD50
NM_005732.4 missense

Scores

3
5
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.95
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3512917).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAD50NM_005732.4 linkuse as main transcriptc.3437T>C p.Ile1146Thr missense_variant 22/25 ENST00000378823.8 NP_005723.2 Q92878-1A5D6Y3
TH2LCRRNR_132124.1 linkuse as main transcriptn.153+996A>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAD50ENST00000378823.8 linkuse as main transcriptc.3437T>C p.Ile1146Thr missense_variant 22/251 NM_005732.4 ENSP00000368100.4 Q92878-1
ENSG00000283782ENST00000640655.2 linkuse as main transcriptc.3140T>C p.Ile1047Thr missense_variant 23/265 ENSP00000491596.2 A0A1W2PQ90

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152098
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
30
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152098
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
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 GeneticsOct 12, 2022The p.I1146T variant (also known as c.3437T>C), located in coding exon 22 of the RAD50 gene, results from a T to C substitution at nucleotide position 3437. The isoleucine at codon 1146 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. 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), LabcorpJul 21, 2023This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1146 of the RAD50 protein (p.Ile1146Thr). This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 480476). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. -
Nijmegen breakage syndrome-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsOct 19, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Uncertain
0.046
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.28
.;.;.;T
Eigen
Benign
0.050
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
.;.;D;D
M_CAP
Benign
0.0080
T
MetaRNN
Benign
0.35
T;T;T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
1.4
.;.;.;L
PrimateAI
Pathogenic
0.92
D
REVEL
Benign
0.18
Sift4G
Uncertain
0.036
.;.;.;D
Polyphen
0.042
.;.;.;B
Vest4
0.67
MutPred
0.48
.;.;.;Loss of stability (P = 0.0037);
MVP
0.78
ClinPred
0.80
D
GERP RS
6.2
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.16
gMVP
0.83

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: rs1554100862; hg19: chr5-131972854; API