rs1555568473
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_002878.4(RAD51D):c.343C>T(p.Gln115Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q115Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002878.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51D | NM_002878.4 | c.343C>T | p.Gln115Ter | stop_gained, splice_region_variant | 4/10 | ENST00000345365.11 | |
RAD51L3-RFFL | NR_037714.1 | n.233-887C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51D | ENST00000345365.11 | c.343C>T | p.Gln115Ter | stop_gained, splice_region_variant | 4/10 | 1 | NM_002878.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 09, 2023 | This missense variant replaces glutamine with a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. In addition, this variant has been shown to affect splicing in a mini-gene assay and in a breast cancer cell line, resulting in multiple abnormal transcripts including out-of-frame deletion of exon 4 or exons 4-5, as well as in-frame deletion of exons 3-5 that encode a functionally important ATPase domain (PMID: 34200360). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2020 | The p.Q115* pathogenic mutation (also known as c.343C>T), located in coding exon 4 of the RAD51D gene, results from a C to T substitution at nucleotide position 343. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 25, 2022 | - - |
Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 04, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change creates a premature translational stop signal (p.Gln115*) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 472599). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at