rs2230017

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_005732.4(RAD50):c.572C>T(p.Thr191Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,612,294 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T191A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0043 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 3 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.50

Publications

18 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 -16 ACMG points.

BP6

Variant 5-132579882-C-T is Benign according to our data. Variant chr5-132579882-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 37382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00433 (659/152218) while in subpopulation AFR AF = 0.0144 (600/41536). AF 95% confidence interval is 0.0135. There are 6 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005732.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.572C>T	p.Thr191Ile	missense	Exon 5 of 25	NP_005723.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAD50	ENST00000378823.8	TSL:1 MANE Select	c.572C>T	p.Thr191Ile	missense	Exon 5 of 25	ENSP00000368100.4	Q92878-1
ENSG00000283782	ENST00000638452.2	TSL:5	c.275C>T	p.Thr92Ile	missense	Exon 7 of 27	ENSP00000492349.2	A0A1W2PQ90
RAD50	ENST00000416135.5	TSL:1	c.275C>T	p.Thr92Ile	missense	Exon 5 of 5	ENSP00000389515.1	C9JNH8

Frequencies

GnomAD3 genomes

AF:

0.00432

AC:

657

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00145

AC:

363

AN:

250440

AF XY:

0.00117

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.00696

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.000665

AC:

971

AN:

1460076

Hom.:

Cov.:

AF XY:

0.000585

AC XY:

425

AN XY:

726454

show subpopulations

African (AFR)

AF:

0.0158

AC:

528

AN:

33410

American (AMR)

AF:

0.000850

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00674

AC:

176

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000104

AC:

116

AN:

1110572

Other (OTH)

AF:

0.00139

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00433

AC:

659

AN:

152218

Hom.:

Cov.:

AF XY:

0.00433

AC XY:

322

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0144

AC:

600

AN:

41536

American (AMR)

AF:

0.00137

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67994

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

121

151

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:

0.00181

Hom.:

Bravo

AF:

0.00487

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00177

AC:

215

Asia WGS

AF:

0.000578

AC:

AN:

3472

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Hereditary cancer-predisposing syndrome (2)

Nijmegen breakage syndrome-like disorder (2)

Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0083

MetaSVM

Benign

-1.2

MutationAssessor

Benign

2.0

PhyloP100

7.5

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.7

REVEL

Benign

0.12

Sift

Benign

0.049

Sift4G

Benign

0.10

Polyphen

0.58

Vest4

0.52

MVP

0.53

ClinPred

0.029

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.50

gMVP

0.35

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 11

DS_AL_spliceai

0.22

Position offset: -20

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over