dbSNP rs780921112: RAD51D:p.Arg239Leu (chr17-35103276-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_002878.4(RAD51D):c.716G>T(p.Arg239Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

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 links:

ENSG00000267618 (HGNC:):

ENSG00000267618 links:

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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 rank	MANE	Protein	UniProt
RAD51D	NM_002878.4 link	c.716G>T	p.Arg239Leu	missense_variant	Exon 8 of 10	ENST00000345365.11	NP_002869.3	O75771-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51D	ENST00000345365.11 link	c.716G>T	p.Arg239Leu	missense_variant	Exon 8 of 10	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 link	c.239G>T	p.Arg80Leu	missense_variant	Exon 4 of 7	2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458652

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725278

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Nov 11, 2019

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RAD51D-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 239 of the RAD51D protein (p.Arg239Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.28

.;.;.;T;T;.;.;.;.;T

Eigen

Benign

-0.044

Eigen_PC

Benign

0.067

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.78

T;T;T;.;T;T;T;T;T;T

M_CAP

Benign

0.061

MetaRNN

Uncertain

0.51

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.9

.;.;.;L;L;.;.;.;.;.

PROVEAN

Uncertain

-3.0

.;.;.;D;.;.;.;.;.;.

REVEL

Benign

0.14

Sift

Benign

0.14

.;.;.;T;.;.;.;.;.;.

Sift4G

Benign

0.19

T;T;D;T;T;T;T;D;D;.

Polyphen

0.012, 0.99

.;.;.;B;B;D;.;.;.;.

Vest4

0.35

MutPred

0.46

.;.;.;Loss of MoRF binding (P = 0.0045);Loss of MoRF binding (P = 0.0045);.;.;.;.;.;

MVP

0.90

MPC

0.44

ClinPred

0.94

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over