14-68594511-G-A

Position:

chr14-68594511-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_133509.5(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. 14/19 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
NM_133509.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.577

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 links:

RAD51B (HGNC:):

RAD51B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 584551.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr14-68594511-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 470 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
RAD51B	NM_133509.5 linkuse as main transcript	c.1063G>A	p.Ala355Thr	missense_variant	11/11	NP_598193.2	O15315-3
RAD51B	NM_001321821.2 linkuse as main transcript	c.1037-16495G>A		intron_variant		NP_001308750.1	C9JYJ0
RAD51B	NM_001321809.2 linkuse as main transcript	c.1037-8152G>A		intron_variant		NP_001308738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
RAD51B	ENST00000487270.5 linkuse as main transcript	c.1063G>A	p.Ala355Thr	missense_variant	11/11	1	ENSP00000419471.1	O15315-3
RAD51B	ENST00000487861.5 linkuse as main transcript	c.1037-16495G>A		intron_variant		1	ENSP00000419881.1	C9JYJ0
RAD51B	ENST00000488612.5 linkuse as main transcript	c.1037-56270G>A		intron_variant		1	ENSP00000420061.1	O15315-4

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

GnomAD3 exomes

AF:

0.00297

AC:

616

AN:

207692

Hom.:

AF XY:

0.00299

AC XY:

345

AN XY:

115274

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 SAS exome

AF:

0.000596

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

Gnomad4 AFR exome

AF:

0.000262

Gnomad4 AMR exome

AF:

0.00180

Gnomad4 ASJ exome

AF:

0.00694

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000718

Gnomad4 FIN exome

AF:

0.00483

Gnomad4 NFE exome

AF:

0.00437

Gnomad4 OTH exome

AF:

0.00354

GnomAD4 genome

AF:

0.00309

AC:

470

AN:

152160

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.000795

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00406

Gnomad4 NFE

AF:

0.00407

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.00295

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneKor MSA

Aug 01, 2018

- -

RAD51B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 25, 2018

- -

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

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

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

Splicing

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