chr5-132604813-T-TA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_005732.4(RAD50):​c.2534dupA​(p.Ile846AspfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K845K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RAD50
NM_005732.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 8.86

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: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-132604813-T-TA is Pathogenic according to our data. Variant chr5-132604813-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 480405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAD50NM_005732.4 linkc.2534dupA p.Ile846AspfsTer2 frameshift_variant Exon 16 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.2534dupA p.Ile846AspfsTer2 frameshift_variant Exon 16 of 25 1 NM_005732.4 ENSP00000368100.4 Q92878-1
ENSG00000283782ENST00000638452.2 linkc.2237dupA p.Ile747AspfsTer2 frameshift_variant Exon 18 of 27 5 ENSP00000492349.2 A0A1W2PQ90

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1456310
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
724712
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33330
American (AMR)
AF:
0.00
AC:
0
AN:
44640
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26076
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39638
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85908
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53334
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.00000181
AC:
2
AN:
1107380
Other (OTH)
AF:
0.00
AC:
0
AN:
60242
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
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
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2
Dec 07, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 480405). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile846Aspfs*2) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 19409520). -

Apr 07, 2017
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2534dupA pathogenic mutation, located in coding exon 16 of the RAD50 gene, results from a duplication of A at nucleotide position 2534, causing a translational frameshift with a predicted alternate stop codon (p.I846Dfs*2). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
8.9
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs1281337925; hg19: chr5-131940505; API