17-35101322-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002878.4(RAD51D):​c.782A>C​(p.Lys261Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,850 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: 0.0000014 ( 0 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

1
7
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.85
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]

Genome browser will be placed here

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 rank MANE Protein UniProt
RAD51DNM_002878.4 linkc.782A>C p.Lys261Thr missense_variant Exon 9 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.782A>C p.Lys261Thr missense_variant Exon 9 of 10 1 NM_002878.4 ENSP00000338790.6 O75771-1
ENSG00000267618ENST00000593039.5 linkc.305A>C p.Lys102Thr missense_variant Exon 5 of 7 2 ENSP00000466834.1 K7EN88

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251406
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461850
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1
Mar 15, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.K261T variant (also known as c.782A>C), located in coding exon 9 of the RAD51D gene, results from an A to C substitution at nucleotide position 782. The lysine at codon 261 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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
May 27, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 410569). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 261 of the RAD51D protein (p.Lys261Thr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Benign
-0.0050
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.31
.;.;.;T;T;.;.;.
Eigen
Benign
0.062
Eigen_PC
Benign
0.052
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.87
D;D;D;.;D;D;D;D
M_CAP
Benign
0.044
D
MetaRNN
Uncertain
0.43
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
0.56
.;.;.;N;N;.;.;.
PROVEAN
Pathogenic
-4.7
.;.;.;D;.;.;.;.
REVEL
Uncertain
0.32
Sift
Uncertain
0.0020
.;.;.;D;.;.;.;.
Sift4G
Uncertain
0.054
T;D;D;D;D;D;D;D
Polyphen
0.85, 1.0
.;.;.;P;P;D;.;.
Vest4
0.71
MutPred
0.63
.;.;.;Loss of catalytic residue at K261 (P = 0.0223);Loss of catalytic residue at K261 (P = 0.0223);.;.;.;
MVP
0.50
MPC
0.42
ClinPred
0.96
D
GERP RS
2.7
Varity_R
0.52
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060502964; hg19: chr17-33428341; API