5-132595759-TAA-TAAA

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_005732.4(RAD50):c.2165dupA(p.Glu723GlyfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,598,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

RAD50
NM_005732.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: -0.126

Publications

27 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: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-132595759-T-TA is Pathogenic according to our data. Variant chr5-132595759-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141045.

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.2165dupA	p.Glu723GlyfsTer5	frameshift	Exon 13 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.2165dupA	p.Glu723GlyfsTer5	frameshift	Exon 13 of 25	ENSP00000368100.4	Q92878-1
ENSG00000283782	ENST00000638452.2	TSL:5	c.1868dupA	p.Glu624GlyfsTer5	frameshift	Exon 15 of 27	ENSP00000492349.2	A0A1W2PQ90
RAD50	ENST00000533482.5	TSL:1	n.*1791dupA		non_coding_transcript_exon	Exon 13 of 25	ENSP00000431225.1	E9PM98

Frequencies

GnomAD3 genomes

AF:

0.000140

AC:

AN:

150326

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000195

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000163

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000271

AC:

AN:

239710

AF XY:

0.000246

show subpopulations

Gnomad AFR exome

AF:

0.000192

Gnomad AMR exome

AF:

0.000242

Gnomad ASJ exome

AF:

0.000205

Gnomad EAS exome

AF:

0.000454

Gnomad FIN exome

AF:

0.000455

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000204

AC:

295

AN:

1447814

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

130

AN XY:

720476

show subpopulations

African (AFR)

AF:

0.000181

AC:

AN:

33082

American (AMR)

AF:

0.000225

AC:

AN:

44356

Ashkenazi Jewish (ASJ)

AF:

0.0000777

AC:

AN:

25730

East Asian (EAS)

AF:

0.000333

AC:

AN:

39036

South Asian (SAS)

AF:

0.000140

AC:

AN:

85836

European-Finnish (FIN)

AF:

0.000287

AC:

AN:

52248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.000201

AC:

222

AN:

1102222

Other (OTH)

AF:

0.000252

AC:

AN:

59602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

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:

0.000140

AC:

AN:

150326

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

73306

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

40944

American (AMR)

AF:

0.000133

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.000195

AC:

AN:

10238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000163

AC:

AN:

67468

Other (OTH)

AF:

0.00

AC:

AN:

2052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.000271

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nijmegen breakage syndrome-like disorder (7)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Breast and/or ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.13

Mutation Taster

=0/200

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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