rs1060501949
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005732.4(RAD50):βc.2985_2989delβ(p.Glu995AspfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,458 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.000022 ( 0 hom. )
Consequence
RAD50
NM_005732.4 frameshift
NM_005732.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.36
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 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 5-132609339-CAAAGA-C is Pathogenic according to our data. Variant chr5-132609339-CAAAGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 408368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.2985_2989del | p.Glu995AspfsTer3 | frameshift_variant | 19/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.2985_2989del | p.Glu995AspfsTer3 | frameshift_variant | 19/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151970Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250904Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135620
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461488Hom.: 0 AF XY: 0.0000261 AC XY: 19AN XY: 727036
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151970Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74204
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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
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2021 | The c.2985_2989delAAAGA pathogenic mutation, located in coding exon 19 of the RAD50 gene, results from a deletion of 5 nucleotides at nucleotide positions 2985 to 2989, causing a translational frameshift with a predicted alternate stop codon (p.E995Dfs*3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | This variant has not been reported in the literature in individuals affected with RAD50-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 408368). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Glu995Aspfs*3) 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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Find out detailed SpliceAI scores and Pangolin per-transcript scores at