rs1060501923
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005732.4(RAD50):c.3370_3373del(p.Tyr1124IlefsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000657 in 152,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
RAD50
NM_005732.4 frameshift
NM_005732.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.47
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 Pathogenic. Variant got 12 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 5-132618270-ATATT-A is Pathogenic according to our data. Variant chr5-132618270-ATATT-A is described in ClinVar as [Pathogenic]. Clinvar id is 408329.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.3370_3373del | p.Tyr1124IlefsTer8 | frameshift_variant | 21/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3370_3373del | p.Tyr1124IlefsTer8 | frameshift_variant | 21/25 | 1 | NM_005732.4 | P1 | |
RAD50 | ENST00000533482.5 | c.*2996_*2999del | 3_prime_UTR_variant, NMD_transcript_variant | 21/25 | 1 | ||||
RAD50 | ENST00000455677.1 | c.5_8del | p.Tyr3IlefsTer8 | frameshift_variant | 1/5 | 5 | |||
RAD50 | ENST00000651249.1 | c.206_209del | p.Tyr70IlefsTer8 | frameshift_variant | 1/6 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 32
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We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74384
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2021 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 408329). 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.Tyr1124Ilefs*8) 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). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at