Genetic Variant RAD51:c.-61G>T (chr15-40695367-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_002875.5(RAD51):c.-61G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 152,416 control chromosomes in the GnomAD database, including 9,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9664 hom., cov: 32)

Exomes 𝑓: 0.39 ( 70 hom. )

Consequence

RAD51
NM_002875.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.808

Publications

101 publications found

Variant links:

Genes affected

RAD51 (HGNC:9817): (RAD51 recombinase) 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, and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with the ssDNA-binding protein RPA and RAD52, and it is thought to play roles in homologous pairing and strand transfer of DNA. This protein is also found to interact with BRCA1 and BRCA2, which may be important for the cellular response to DNA damage. BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of this protein. Loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

RAD51 links:

RAD51-AS1 (HGNC:48621): (RAD51 antisense RNA 1)

RAD51-AS1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 15-40695367-G-T is Benign according to our data. Variant chr15-40695367-G-T is described in ClinVar as Benign. ClinVar VariationId is 1243349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51	NM_002875.5 link	c.-61G>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000267868.8	NP_002866.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RAD51	ENST00000267868.8 link	c.-61G>T	5_prime_UTR_variant	Exon 1 of 10	1	NM_002875.5	ENSP00000267868.3
RAD51	ENST00000557850.5 link	c.-61G>T	5_prime_UTR_variant	Exon 1 of 8	2		ENSP00000454176.1
RAD51	ENST00000532743.6 link	c.-262G>T	upstream_gene_variant		2		ENSP00000433924.2

Frequencies

GnomAD3 genomes

AF:

0.346

AC:

52361

AN:

151434

Hom.:

9666

Cov.:

show subpopulations

Gnomad AFR

AF:

0.283

Gnomad AMI

AF:

0.369

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.390

Gnomad EAS

AF:

0.0772

Gnomad SAS

AF:

0.234

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.421

Gnomad OTH

AF:

0.371

GnomAD4 exome

AF:

0.385

AC:

332

AN:

862

Hom.:

Cov.:

AF XY:

0.385

AC XY:

265

AN XY:

688

show subpopulations

African (AFR)

AF:

0.100

AC:

AN:

American (AMR)

AF:

0.375

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.136

AC:

AN:

South Asian (SAS)

AF:

0.0909

AC:

AN:

European-Finnish (FIN)

AF:

0.286

AC:

AN:

Middle Eastern (MID)

AF:

0.833

AC:

AN:

European-Non Finnish (NFE)

AF:

0.408

AC:

305

AN:

748

Other (OTH)

AF:

0.208

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.345

AC:

52360

AN:

151554

Hom.:

9664

Cov.:

AF XY:

0.337

AC XY:

24977

AN XY:

74104

show subpopulations

African (AFR)

AF:

0.283

AC:

11704

AN:

41380

American (AMR)

AF:

0.313

AC:

4759

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

1353

AN:

3470

East Asian (EAS)

AF:

0.0766

AC:

383

AN:

5002

South Asian (SAS)

AF:

0.234

AC:

1096

AN:

4674

European-Finnish (FIN)

AF:

0.306

AC:

3244

AN:

10584

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.421

AC:

28605

AN:

67900

Other (OTH)

AF:

0.368

AC:

777

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1759

3517

5276

7034

8793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

508

1016

1524

2032

2540

<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:

0.366

Hom.:

1301

Bravo

AF:

0.340

Asia WGS

AF:

0.150

AC:

523

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16398215, 22613844, 17118968)

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.8

(source)

DANN

Benign

0.62

PhyloP100

-0.81

PromoterAI

-0.073

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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