rs1423695400
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_002878.4(RAD51D):c.946_947insA(p.Thr316AsnfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T316T) has been classified as Likely benign.
Frequency
Consequence
NM_002878.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51D | NM_002878.4 | c.946_947insA | p.Thr316AsnfsTer11 | frameshift_variant | 10/10 | ENST00000345365.11 | |
RAD51L3-RFFL | NR_037714.1 | n.655+207_655+208insA | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51D | ENST00000345365.11 | c.946_947insA | p.Thr316AsnfsTer11 | frameshift_variant | 10/10 | 1 | NM_002878.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251490Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461472Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727066
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 04, 2023 | This variant inserts 1 nucleotide in exon 10 of the RAD51D gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein. This variant is expected to disrupt the amino acid residues Thr316 through Thr328 of the RAD51D protein that encode the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057) and RAD51C interaction domain (PMID: 10749867, 14704354, 19327148). To our knowledge, functional studies have not been reported for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been observed together with a pathogenic BRCA2 truncation variant in an individual with a strong family history of breast cancers (Color internal data). This variant has been identified in 1/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2022 | The c.946dupA variant, located in coding exon 10 of the RAD51D gene, results from a duplication of A at nucleotide position 946, causing a translational frameshift with a predicted alternate stop codon (p.T316Nfs*11). This alteration occurs at the 3' terminus of theRAD51D gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 13 amino acids (4%) of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 25, 2020 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 490149). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the RAD51D gene (p.Thr316Asnfs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 13 amino acids of the RAD51D protein. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at