rs1060502958
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_002878.4(RAD51D):c.728_729insT(p.Met243IlefsTer84) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
RAD51D
NM_002878.4 frameshift
NM_002878.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.98
Genes affected
RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-35103263-C-CA is Pathogenic according to our data. Variant chr17-35103263-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410560.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51D | NM_002878.4 | c.728_729insT | p.Met243IlefsTer84 | frameshift_variant | 8/10 | ENST00000345365.11 | |
RAD51L3-RFFL | NR_037714.1 | n.480_481insT | non_coding_transcript_exon_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51D | ENST00000345365.11 | c.728_729insT | p.Met243IlefsTer84 | frameshift_variant | 8/10 | 1 | NM_002878.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 22, 2017 | In summary, this variant is a rare frameshift variant that is expected to disrupt an important functional domain of the RAD51D protein. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This frameshift is expected to partially disrupt the C-terminus of the ATPase domain of the RAD51D protein (PMID: 14704354, 19327148, 21111057), which is required for interacting with RAD51C to assist DNA repair activity (PMID: 14704354, 19327148). While functional studies have not been reported for this particular variant, a truncating variant in the C- terminal region was found to segregate in three family members with ovarian cancer and family history of ovarian and breast cancers (Invitae database), suggesting that disruption of this region of the RAD51D protein is causative of disease. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RAD51D-related disease. This sequence change inserts 1 nucleotide in exon 8 of the RAD51D mRNA (c.728dupT), causing a frameshift at codon 243. This creates a premature translational stop signal in the last exon of the RAD51D mRNA (p.Met243Ilefs*84). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acids of the RAD51D protein. - |
Computational scores
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Calibrated prediction
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Prediction
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