NM_005732.4:c.280A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005732.4(RAD50):c.280A>C(p.Ile94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,602,792 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I94M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 25 hom. )

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0120

Publications

28 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056197047).

BP6

Variant 5-132575843-A-C is Benign according to our data. Variant chr5-132575843-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 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.280A>C	p.Ile94Leu	missense	Exon 3 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.280A>C	p.Ile94Leu	missense	Exon 3 of 25	ENSP00000368100.4	Q92878-1
ENSG00000283782	ENST00000638452.2	TSL:5	c.-18A>C		5_prime_UTR	Exon 5 of 27	ENSP00000492349.2	A0A1W2PQ90
RAD50	ENST00000416135.5	TSL:1	c.-18A>C		5_prime_UTR	Exon 3 of 5	ENSP00000389515.1	C9JNH8

Frequencies

GnomAD3 genomes

AF:

0.00319

AC:

485

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00497

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00343

AC:

863

AN:

251344

AF XY:

0.00348

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00415

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00457

AC:

6633

AN:

1450440

Hom.:

Cov.:

AF XY:

0.00456

AC XY:

3294

AN XY:

722270

show subpopulations

African (AFR)

AF:

0.000843

AC:

AN:

33220

American (AMR)

AF:

0.00268

AC:

120

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00514

AC:

134

AN:

26070

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39618

South Asian (SAS)

AF:

0.00555

AC:

477

AN:

86020

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00644

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00501

AC:

5516

AN:

1101640

Other (OTH)

AF:

0.00438

AC:

263

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

333

666

998

1331

1664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

224

448

672

896

1120

<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:

0.00318

AC:

484

AN:

152352

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

229

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41586

American (AMR)

AF:

0.00294

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00497

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00497

AC:

338

AN:

68032

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

101

126

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:

0.00425

Hom.:

Bravo

AF:

0.00328

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00347

AC:

421

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00557

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nijmegen breakage syndrome-like disorder (5)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

not specified (2)

Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.4

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.063

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.71

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.70

PhyloP100

-0.012

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

REVEL

Benign

0.071

Sift

Benign

0.35

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.17

MutPred

0.48

Loss of catalytic residue at I94 (P = 0.0063)

MVP

0.23

ClinPred

0.0039

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.070

gMVP

0.46

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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