ENST00000487270.5:c.1063G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000487270.5(RAD51B):c.1063G>A(p.Ala355Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,364,372 control chromosomes in the GnomAD database, including 16 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 15 hom. )

Consequence

RAD51B
ENST00000487270.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.577

Publications

11 publications found

Variant links:

Genes affected

RAD51B (HGNC:9822): (RAD51 paralog B) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are evolutionarily conserved proteins essential for DNA repair by homologous recombination. This protein has been shown to form a stable heterodimer with the family member RAD51C, which further interacts with the other family members, such as RAD51, XRCC2, and XRCC3. Overexpression of this gene was found to cause cell cycle G1 delay and cell apoptosis, which suggested a role of this protein in sensing DNA damage. Rearrangements between this locus and high mobility group AT-hook 2 (HMGA2, GeneID 8091) have been observed in uterine leiomyomata. [provided by RefSeq, Mar 2016]

RAD51B Gene-Disease associations (from GenCC):

primary ovarian failure
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

RAD51B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003962934).

BP6

Variant 14-68594511-G-A is Benign according to our data. Variant chr14-68594511-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 584551.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
RAD51B	NM_133509.5 link	c.1063G>A	p.Ala355Thr	missense_variant	Exon 11 of 11	NP_598193.2
RAD51B	NM_001321821.2 link	c.1037-16495G>A		intron_variant	Intron 10 of 10	NP_001308750.1
RAD51B	NM_001321809.2 link	c.1037-8152G>A		intron_variant	Intron 10 of 11	NP_001308738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein
RAD51B	ENST00000487270.5 link	c.1063G>A	p.Ala355Thr	missense_variant	Exon 11 of 11	1	ENSP00000419471.1
RAD51B	ENST00000487861.5 link	c.1037-16495G>A		intron_variant	Intron 10 of 10	1	ENSP00000419881.1
RAD51B	ENST00000488612.5 link	c.1037-56270G>A		intron_variant	Intron 10 of 11	1	ENSP00000420061.1

Frequencies

GnomAD3 genomes

AF:

0.00310

AC:

472

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00544

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00406

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00409

Gnomad OTH

AF:

0.00719

GnomAD2 exomes

AF:

0.00297

AC:

616

AN:

207692

AF XY:

0.00299

show subpopulations

Gnomad AFR exome

AF:

0.000649

Gnomad AMR exome

AF:

0.00175

Gnomad ASJ exome

AF:

0.00704

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00480

Gnomad NFE exome

AF:

0.00430

Gnomad OTH exome

AF:

0.00295

GnomAD4 exome

AF:

0.00387

AC:

4695

AN:

1212212

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

2209

AN XY:

599632

show subpopulations

African (AFR)

AF:

0.000262

AC:

AN:

26714

American (AMR)

AF:

0.00180

AC:

AN:

36168

Ashkenazi Jewish (ASJ)

AF:

0.00694

AC:

126

AN:

18146

East Asian (EAS)

AF:

0.00

AC:

AN:

21452

South Asian (SAS)

AF:

0.000718

AC:

AN:

82218

European-Finnish (FIN)

AF:

0.00483

AC:

AN:

16566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4310

European-Non Finnish (NFE)

AF:

0.00437

AC:

4198

AN:

961390

Other (OTH)

AF:

0.00354

AC:

160

AN:

45248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

221

442

662

883

1104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00309

AC:

470

AN:

152160

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.000795

AC:

AN:

41512

American (AMR)

AF:

0.00536

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00406

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00407

AC:

277

AN:

67998

Other (OTH)

AF:

0.00712

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00312

Hom.:

Bravo

AF:

0.00312

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000962

AC:

ESP6500EA

AF:

0.00327

AC:

ExAC

AF:

0.00278

AC:

316

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 01, 2018

GeneKor MSA

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RAD51B-related disorder

Benign:1

Jul 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Feb 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.56

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.032

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.47

M_CAP

Benign

0.0017

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.26

PhyloP100

-0.58

PrimateAI

Benign

0.33

PROVEAN

Benign

0.25

REVEL

Benign

0.019

Sift

Benign

0.14

Sift4G

Benign

0.23

Polyphen

0.23

Vest4

0.11

MVP

0.13

MPC

0.26

ClinPred

0.0018

GERP RS

0.65

Varity_R

0.10

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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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