rs867328327
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005732.4(RAD50):c.94dup(p.Thr32AsnfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L31L) has been classified as Likely benign.
Frequency
Consequence
NM_005732.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.94dup | p.Thr32AsnfsTer16 | frameshift_variant | 1/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.94dup | p.Thr32AsnfsTer16 | frameshift_variant | 1/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251276Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135828
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461826Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 727216
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74378
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change creates a premature translational stop signal (p.Thr32Asnfs*16) 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). This variant is present in population databases (rs587781625, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 141279). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 17, 2013 | The c.94dupA pathogenic mutation, located in coding exon 1 of the RAD50 gene, results from a duplication of one nucleotide at position 94, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Nijmegen breakage syndrome-like disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 17, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 06, 2023 | - - |
RAD50-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 20, 2023 | The RAD50 c.94dupA variant is predicted to result in a frameshift and premature protein termination (p.Thr32Asnfs*16). This variant has been reported in large population studies and carrier testing screens, where the phenotype of individuals is not known (LaDuca et al. 2017. PubMed ID: 28152038; Capalbo et al. 2019. PubMed ID: 31589614). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131893109-T-TA). Frameshift variants in RAD50 are expected to be pathogenic and this variant has been classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141279/). This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at