chr5-132588018-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005732.4(RAD50):c.980G>A(p.Arg327His) variant causes a missense change. The variant allele was found at a frequency of 0.00257 in 1,611,958 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R327G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 24 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 6.21

Publications

30 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049374104).

BP6

Variant 5-132588018-G-A is Benign according to our data. Variant chr5-132588018-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 37380.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00261 (3806/1459672) while in subpopulation SAS AF = 0.00797 (687/86196). AF 95% confidence interval is 0.00748. There are 24 homozygotes in GnomAdExome4. There are 2092 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 24 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.980G>A	p.Arg327His	missense	Exon 7 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.980G>A	p.Arg327His	missense	Exon 7 of 25	ENSP00000368100.4	Q92878-1
ENSG00000283782	ENST00000638452.2	TSL:5	c.683G>A	p.Arg228His	missense	Exon 9 of 27	ENSP00000492349.2	A0A1W2PQ90
RAD50	ENST00000533482.5	TSL:1	n.*606G>A		non_coding_transcript_exon	Exon 7 of 25	ENSP00000431225.1	E9PM98

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

342

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00300

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00346

AC:

865

AN:

249856

AF XY:

0.00394

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00326

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00261

AC:

3806

AN:

1459672

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

2092

AN XY:

726296

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33420

American (AMR)

AF:

0.00168

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

408

AN:

26110

East Asian (EAS)

AF:

0.000101

AC:

AN:

39578

South Asian (SAS)

AF:

0.00797

AC:

687

AN:

86196

European-Finnish (FIN)

AF:

0.000731

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00781

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00208

AC:

2310

AN:

1110210

Other (OTH)

AF:

0.00376

AC:

227

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

190

379

569

758

948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.00224

AC:

341

AN:

152286

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41568

American (AMR)

AF:

0.000980

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00685

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00300

AC:

204

AN:

68016

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00319

Hom.:

Bravo

AF:

0.00225

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00350

AC:

425

Asia WGS

AF:

0.00260

AC:

AN:

3470

EpiCase

AF:

0.00338

EpiControl

AF:

0.00338

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (4)

not provided (3)

Nijmegen breakage syndrome-like disorder (2)

not specified (2)

RAD50-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0064

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

PhyloP100

6.2

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.21

Sift

Benign

0.063

Sift4G

Uncertain

0.022

Polyphen

0.99

Vest4

0.23

MVP

0.71

ClinPred

0.032

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.17

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over