17-35106468-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002878.4(RAD51D):c.494G>A(p.Arg165Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,611,192 control chromosomes in the GnomAD database, including 17,336 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 1455 hom., cov: 32)

Exomes 𝑓: 0.14 ( 15881 hom. )

Consequence

RAD51D
NM_002878.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.18

Publications

53 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

RAD51D links:

ENSG00000267618 (HGNC:):

ENSG00000267618 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022848845).

BP6

Variant 17-35106468-C-T is Benign according to our data. Variant chr17-35106468-C-T is described in ClinVar as Benign. ClinVar VariationId is 142159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51D	NM_002878.4 link	c.494G>A	p.Arg165Gln	missense_variant	Exon 6 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.494G>A	p.Arg165Gln	missense_variant	Exon 6 of 10	1	NM_002878.4	ENSP00000338790.6		O75771-1
ENSG00000267618	ENST00000593039.5 link	c.17G>A	p.Arg6Gln	missense_variant	Exon 2 of 7	2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18421

AN:

152092

Hom.:

1452

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0335

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.217

Gnomad ASJ

AF:

0.205

Gnomad EAS

AF:

0.0458

Gnomad SAS

AF:

0.144

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.144

Gnomad OTH

AF:

0.118

GnomAD2 exomes

AF:

0.156

AC:

38415

AN:

247030

AF XY:

0.154

show subpopulations

Gnomad AFR exome

AF:

0.0296

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.190

Gnomad EAS exome

AF:

0.0455

Gnomad FIN exome

AF:

0.169

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.141

AC:

205147

AN:

1458982

Hom.:

15881

Cov.:

AF XY:

0.141

AC XY:

102408

AN XY:

725640

show subpopulations

African (AFR)

AF:

0.0265

AC:

887

AN:

33438

American (AMR)

AF:

0.285

AC:

12638

AN:

44354

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

5050

AN:

25976

East Asian (EAS)

AF:

0.0429

AC:

1702

AN:

39692

South Asian (SAS)

AF:

0.163

AC:

14025

AN:

85796

European-Finnish (FIN)

AF:

0.166

AC:

8846

AN:

53290

Middle Eastern (MID)

AF:

0.129

AC:

744

AN:

5758

European-Non Finnish (NFE)

AF:

0.138

AC:

153134

AN:

1110356

Other (OTH)

AF:

0.135

AC:

8121

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

8867

17734

26602

35469

44336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5432

10864

16296

21728

27160

<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

AF:

0.121

AC:

18427

AN:

152210

Hom.:

1455

Cov.:

AF XY:

0.125

AC XY:

9284

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0335

AC:

1393

AN:

41536

American (AMR)

AF:

0.217

AC:

3326

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

712

AN:

3470

East Asian (EAS)

AF:

0.0459

AC:

238

AN:

5184

South Asian (SAS)

AF:

0.144

AC:

696

AN:

4818

European-Finnish (FIN)

AF:

0.178

AC:

1886

AN:

10600

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.144

AC:

9794

AN:

67994

Other (OTH)

AF:

0.117

AC:

247

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

801

1603

2404

3206

4007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.136

Hom.:

7501

Bravo

AF:

0.120

TwinsUK

AF:

0.143

AC:

531

ALSPAC

AF:

0.131

AC:

504

ESP6500AA

AF:

0.0368

AC:

162

ESP6500EA

AF:

0.143

AC:

1227

ExAC

AF:

0.148

AC:

17916

Asia WGS

AF:

0.0980

AC:

343

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

Benign:5

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2016

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 10, 2023

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28202063) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary cancer-predisposing syndrome

Benign:2

Nov 05, 2014

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.074

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.65

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

MetaRNN

Benign

0.0023

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

.;.;N;N;.;.;.;.

PhyloP100

1.2

PROVEAN

Benign

1.6

.;.;N;D;.;.;.;.

REVEL

Benign

0.13

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0, 0.0080

.;.;B;B;B;.;.;.

Vest4

0.080

MPC

0.41

ClinPred

0.0074

GERP RS

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.051

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over