rs1555567197
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002878.4(RAD51D):c.740_741dupTG(p.Thr248fs) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V247V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
RAD51D
NM_002878.4 frameshift, splice_region
NM_002878.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.34
Publications
1 publications found
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]
RAD51D Gene-Disease associations (from GenCC):
- breast-ovarian cancer, familial, susceptibility to, 4Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary breast carcinomaInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 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 17-35101362-T-TCA is Pathogenic according to our data. Variant chr17-35101362-T-TCA is described in ClinVar as Pathogenic. ClinVar VariationId is 548817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_002878.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RAD51D | NM_002878.4 | MANE Select | c.740_741dupTG | p.Thr248fs | frameshift splice_region | Exon 9 of 10 | NP_002869.3 | ||
| RAD51D | NM_001142571.2 | c.800_801dupTG | p.Thr268fs | frameshift splice_region | Exon 9 of 10 | NP_001136043.1 | |||
| RAD51D | NM_133629.3 | c.404_405dupTG | p.Thr136fs | frameshift splice_region | Exon 6 of 7 | NP_598332.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RAD51D | ENST00000345365.11 | TSL:1 MANE Select | c.740_741dupTG | p.Thr248fs | frameshift splice_region | Exon 9 of 10 | ENSP00000338790.6 | ||
| RAD51D | ENST00000586186.3 | TSL:1 | c.605_606dupTG | p.Thr203fs | frameshift splice_region | Exon 8 of 9 | ENSP00000468273.3 | ||
| ENSG00000267618 | ENST00000593039.5 | TSL:2 | c.263_264dupTG | p.Thr89fs | frameshift splice_region | Exon 5 of 7 | ENSP00000466834.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461358Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726946 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461358
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
726946
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33476
American (AMR)
AF:
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
52940
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111976
Other (OTH)
AF:
AC:
0
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
Breast-ovarian cancer, familial, susceptibility to, 4 (2)
1
-
-
Hereditary cancer-predisposing syndrome (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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