rs753393344
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_133510.4(RAD51B):c.452+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000523 in 1,586,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000046 ( 0 hom., cov: 27)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
RAD51B
NM_133510.4 splice_donor_region, intron
NM_133510.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9534
2
Clinical Significance
Conservation
PhyloP100: 0.990
Genes affected
RAD51B (HGNC:9822): (RAD51 paralog B) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are evolutionarily conserved proteins essential for DNA repair by homologous recombination. This protein has been shown to form a stable heterodimer with the family member RAD51C, which further interacts with the other family members, such as RAD51, XRCC2, and XRCC3. Overexpression of this gene was found to cause cell cycle G1 delay and cell apoptosis, which suggested a role of this protein in sensing DNA damage. Rearrangements between this locus and high mobility group AT-hook 2 (HMGA2, GeneID 8091) have been observed in uterine leiomyomata. [provided by RefSeq, Mar 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
?
Variant 14-67865142-A-G is Benign according to our data. Variant chr14-67865142-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224592.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
?
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51B | NM_133510.4 | c.452+3A>G | splice_donor_region_variant, intron_variant | ENST00000471583.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51B | ENST00000471583.6 | c.452+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_133510.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000462 AC: 7AN: 151482Hom.: 0 Cov.: 27
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GnomAD3 exomes AF: 0.0000864 AC: 20AN: 231560Hom.: 0 AF XY: 0.0000797 AC XY: 10AN XY: 125540
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GnomAD4 exome AF: 0.0000530 AC: 76AN: 1435296Hom.: 0 Cov.: 33 AF XY: 0.0000490 AC XY: 35AN XY: 713890
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GnomAD4 genome ? AF: 0.0000462 AC: 7AN: 151482Hom.: 0 Cov.: 27 AF XY: 0.0000406 AC XY: 3AN XY: 73968
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 26, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Oct 22, 2019 | This variant was predicted to disrupt a splice donor site, resulting in skipping of exon 5 and production of abnormally short protein. This variant has been reported in a patient with a family history of breast cancer and loss of RAD51B expression (Golmard 2013). However, this variant is found in approximately 1/6000 individuals in the population. It has also been detected in three women over age 70 with no history of cancer (https://whi.color.com/) and 20 individuals in an unaffected control population (gnomAD). The presence of this variant at this frequency in unaffected women indicates that it does not substantially increase cancer risk. - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at