chr5-132609361-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005732.4(RAD50):​c.3001A>T​(p.Met1001Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1001T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

1
1
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.72

Publications

0 publications found
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]
RAD50 Gene-Disease associations (from GenCC):
  • Nijmegen breakage syndrome-like disorder
    Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
  • familial ovarian cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
  • hereditary breast carcinoma
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32685304).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAD50NM_005732.4 linkc.3001A>T p.Met1001Leu missense_variant Exon 19 of 25 ENST00000378823.8 NP_005723.2 Q92878-1A5D6Y3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAD50ENST00000378823.8 linkc.3001A>T p.Met1001Leu missense_variant Exon 19 of 25 1 NM_005732.4 ENSP00000368100.4 Q92878-1
ENSG00000283782ENST00000638452.2 linkc.2704A>T p.Met902Leu missense_variant Exon 21 of 27 5 ENSP00000492349.2 A0A1W2PQ90

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461546
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727068
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26122
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39602
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86234
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53402
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111856
Other (OTH)
AF:
0.00
AC:
0
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.0099
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
21
DANN
Benign
0.96
DEOGEN2
Benign
0.064
.;.;.;T
Eigen
Benign
-0.10
Eigen_PC
Benign
0.096
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.75
.;.;T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.33
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
2.0
.;.;.;M
PhyloP100
8.7
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-2.4
.;.;.;N
REVEL
Benign
0.22
Sift
Benign
0.14
.;.;.;T
Sift4G
Benign
0.91
.;.;.;T
Polyphen
0.0070
.;.;.;B
Vest4
0.55
MutPred
0.48
.;.;.;Loss of MoRF binding (P = 0.0831);
MVP
0.57
ClinPred
0.86
D
GERP RS
5.1
Varity_R
0.21
gMVP
0.45
Mutation Taster
=80/20
polymorphism

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

Other links and lift over

dbSNP: rs876660064; hg19: chr5-131945053; API