chr14-67887067-G-T

Position:

chr14-67887067-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_133510.4(RAD51B):c.619G>T(p.Val207Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,563,044 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 8 hom. )

Consequence

RAD51B
NM_133510.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.19

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011664689).

BS2

High AC in GnomAd4 at 336 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51B	NM_133510.4 linkuse as main transcript	c.619G>T	p.Val207Leu	missense_variant	7/11	ENST00000471583.6	NP_598194.1	O15315-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51B	ENST00000471583.6 linkuse as main transcript	c.619G>T	p.Val207Leu	missense_variant	7/11	1	NM_133510.4	ENSP00000418859.1		O15315-2

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

336

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00401

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00164

AC:

395

AN:

240472

Hom.:

AF XY:

0.00156

AC XY:

203

AN XY:

129744

show subpopulations

Gnomad AFR exome

AF:

0.00106

Gnomad AMR exome

AF:

0.00144

Gnomad ASJ exome

AF:

0.000210

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00290

Gnomad OTH exome

AF:

0.000847

GnomAD4 exome

AF:

0.00303

AC:

4277

AN:

1410806

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

2030

AN XY:

703024

show subpopulations

Gnomad4 AFR exome

AF:

0.000907

Gnomad4 AMR exome

AF:

0.00151

Gnomad4 ASJ exome

AF:

0.000355

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00374

Gnomad4 OTH exome

AF:

0.00241

GnomAD4 genome

AF:

0.00221

AC:

336

AN:

152238

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00401

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.00251

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00137

AC:

167

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneKor MSA

Aug 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.011

T;.;T;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.043

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.84

T;T;T;T;T

M_CAP

Benign

0.0099

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.59

.;N;N;.;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.60

N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.41

T;T;T;T;T

Sift4G

Benign

0.18

T;T;T;T;T

Polyphen

0.11

B;B;B;.;B

Vest4

0.38

MutPred

0.49

Gain of catalytic residue at V207 (P = 0.0019);Gain of catalytic residue at V207 (P = 0.0019);Gain of catalytic residue at V207 (P = 0.0019);Gain of catalytic residue at V207 (P = 0.0019);Gain of catalytic residue at V207 (P = 0.0019);

MVP

0.61

MPC

0.25

ClinPred

0.013

GERP RS

4.8

Varity_R

0.11

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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