chr17-35119119-A-G
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002878.4(RAD51D):c.136T>C(p.Ser46Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,308 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
RAD51D
NM_002878.4 missense
NM_002878.4 missense
Scores
2
10
6
Clinical Significance
Conservation
PhyloP100: 7.01
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAD51D | NM_002878.4 | c.136T>C | p.Ser46Pro | missense_variant | 2/10 | ENST00000345365.11 | NP_002869.3 | |
RAD51L3-RFFL | NR_037714.1 | n.232+2172T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD51D | ENST00000345365.11 | c.136T>C | p.Ser46Pro | missense_variant | 2/10 | 1 | NM_002878.4 | ENSP00000338790 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461308Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727000
GnomAD4 exome
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1461308
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31
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1
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727000
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
EpiCase
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2022 | The p.S46P variant (also known as c.136T>C), located in coding exon 2 of the RAD51D gene, results from a T to C substitution at nucleotide position 136. The serine at codon 46 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 08, 2020 | This missense variant replaces serine with proline at codon 46 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. - |
Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 07, 2023 | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 480525). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 46 of the RAD51D protein (p.Ser46Pro). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 06, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21111057) - |
RAD51D-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 09, 2022 | The RAD51D c.136T>C variant is predicted to result in the amino acid substitution p.Ser46Pro. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/480525/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M;.
MutationTaster
Benign
D;D;D;D;D;D;N
PROVEAN
Uncertain
D;D;D;.;.
REVEL
Uncertain
Sift
Benign
T;T;T;.;.
Sift4G
Benign
T;T;D;T;.
Polyphen
B;B;D;.;.
Vest4
MutPred
Gain of helix (P = 0.005);Gain of helix (P = 0.005);Gain of helix (P = 0.005);Gain of helix (P = 0.005);.;
MVP
MPC
0.13
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at