rs876658212
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_005732.4(RAD50):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
RAD50
NM_005732.4 start_lost
NM_005732.4 start_lost
Scores
6
6
3
Clinical Significance
Conservation
PhyloP100: 9.10
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 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_005732.4 (RAD50) was described as [Likely_pathogenic] in ClinVar as 128024
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-132557325-A-G is Pathogenic according to our data. Variant chr5-132557325-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 229813.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.1A>G | p.Met1? | start_lost | 1/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.1A>G | p.Met1? | start_lost | 1/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 229813). A different variant (c.3G>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 26023681, 26094658; Invitae). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the RAD50 mRNA. The next in-frame methionine is located at codon 7. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 23, 2016 | The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the RAD50 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. However, the RAD50 gene contains a second methionine 21 nucleotides (seven amino acids) downstream of the canonical start site. This has the potential to function as an alternate translation initiation site, resulting in the removal of the first six amino acids from protein, however, direct evidence is unavailable. A similar alteration at the same initiation codon, p.M1? (c.3G>A), has been reported in 1/104 Irish familial breast cancer families and 0/140 controls (Aloraifi F et al. FEBS J., 2015 Sep;282:3424-37), and has also been reported in conjunction with a BRCA2 mutation in an individual diagnosed with breast cancer at age 49 (Foley SB et al. EBioMedicine, 2015 Jan;2:74-81). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, the p.M1? variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Benign
N;D
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at