NM_002878.4:c.305T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002878.4(RAD51D):​c.305T>G​(p.Val102Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000212 in 1,414,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V102M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

10
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.51

Publications

0 publications found
Variant links:
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, 4
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • hereditary breast ovarian cancer syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary breast carcinoma
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAD51DNM_002878.4 linkc.305T>G p.Val102Gly missense_variant Exon 4 of 10 ENST00000345365.11 NP_002869.3 O75771-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAD51DENST00000345365.11 linkc.305T>G p.Val102Gly missense_variant Exon 4 of 10 1 NM_002878.4 ENSP00000338790.6 O75771-1
ENSG00000267618ENST00000593039.5 linkc.4-925T>G intron_variant Intron 1 of 6 2 ENSP00000466834.1 K7EN88

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000212
AC:
3
AN:
1414258
Hom.:
0
Cov.:
31
AF XY:
0.00000142
AC XY:
1
AN XY:
705920
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32342
American (AMR)
AF:
0.00
AC:
0
AN:
44654
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25886
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39476
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85234
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5678
European-Non Finnish (NFE)
AF:
0.00000281
AC:
3
AN:
1068740
Other (OTH)
AF:
0.00
AC:
0
AN:
58838
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
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
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:1
Jun 28, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 102 of the RAD51D protein (p.Val102Gly). 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: 539850). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAD51D protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T;T;.;T
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.80
.;T;T;T
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.88
D;D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Pathogenic
3.6
H;H;.;.
PhyloP100
6.5
PROVEAN
Pathogenic
-5.5
D;.;.;.
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0010
D;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;.
Polyphen
0.98
D;D;.;.
Vest4
0.73
MutPred
0.72
Gain of disorder (P = 0.0108);Gain of disorder (P = 0.0108);.;.;
MVP
0.97
MPC
0.51
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.97
gMVP
0.91
Mutation Taster
=59/41
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1555568494; hg19: chr17-33434425; API