rs28903094
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_005732.4(RAD50):c.3879C>T(p.Ile1293=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,613,892 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0042 ( 16 hom. )
Consequence
RAD50
NM_005732.4 synonymous
NM_005732.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.48
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 Benign. Variant got -10 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
Variant 5-132642304-C-T is Benign according to our data. Variant chr5-132642304-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37384.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=3, Uncertain_significance=1}. Variant chr5-132642304-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-1.48 with no splicing effect.
BS2
?
High Homozygotes in GnomAd4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.3879C>T | p.Ile1293= | synonymous_variant | 25/25 | ENST00000378823.8 | |
TH2LCRR | NR_132125.1 | n.105-22G>A | intron_variant, non_coding_transcript_variant | ||||
TH2LCRR | NR_132126.1 | n.175-4039G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3879C>T | p.Ile1293= | synonymous_variant | 25/25 | 1 | NM_005732.4 | P1 | |
TH2LCRR | ENST00000435042.1 | n.95-22G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00276 AC: 419AN: 152078Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00249 AC: 626AN: 251256Hom.: 2 AF XY: 0.00242 AC XY: 328AN XY: 135792
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GnomAD4 exome AF: 0.00425 AC: 6206AN: 1461696Hom.: 16 Cov.: 31 AF XY: 0.00411 AC XY: 2989AN XY: 727160
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GnomAD4 genome ? AF: 0.00275 AC: 419AN: 152196Hom.: 2 Cov.: 32 AF XY: 0.00266 AC XY: 198AN XY: 74420
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 05, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 19, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
not provided Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 16, 2017 | Variant summary: The RAD50 c.3879C>T (p.Ile1293Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 266/121258 control chromosomes (1 homozygote) at a frequency of 0.0021937, which is approximately 35 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | RAD50: BP4, BP7, BS2 - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Nijmegen breakage syndrome-like disorder Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Aug 22, 2016 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 22, 2020 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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