Genetic Variant RAD50:c.3037-2804A>G (chr5-132613199-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005732.4(RAD50):c.3037-2804A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,062 control chromosomes in the GnomAD database, including 2,478 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2478 hom., cov: 31)

Consequence

RAD50
NM_005732.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0870

Publications

14 publications found

Variant links:

Genes affected

RAD50 (HGNC:9816): (RAD50 double strand break repair protein) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]

RAD50 Gene-Disease associations (from GenCC):

Nijmegen breakage syndrome-like disorder
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RAD50 links:

ENSG00000283782 (HGNC:):

ENSG00000283782 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4 link	c.3037-2804A>G		intron_variant	Intron 19 of 24	ENST00000378823.8	NP_005723.2	Q92878-1A5D6Y3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 link	c.3037-2804A>G		intron_variant	Intron 19 of 24	1	NM_005732.4	ENSP00000368100.4		Q92878-1
ENSG00000283782	ENST00000638452.2 link	c.2740-2804A>G		intron_variant	Intron 21 of 26	5		ENSP00000492349.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26112

AN:

151944

Hom.:

2476

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0926

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.189

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.230

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.176

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.172

AC:

26112

AN:

152062

Hom.:

2478

Cov.:

AF XY:

0.173

AC XY:

12871

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0924

AC:

3833

AN:

41482

American (AMR)

AF:

0.143

AC:

2185

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

799

AN:

3470

East Asian (EAS)

AF:

0.190

AC:

985

AN:

5182

South Asian (SAS)

AF:

0.225

AC:

1080

AN:

4810

European-Finnish (FIN)

AF:

0.230

AC:

2427

AN:

10552

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.210

AC:

14265

AN:

67980

Other (OTH)

AF:

0.174

AC:

367

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1089

2177

3266

4354

5443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.189

Hom.:

1336

Bravo

AF:

0.159

Asia WGS

AF:

0.190

AC:

663

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

1.9

(source)

DANN

Benign

0.34

PhyloP100

-0.087

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over