chr5-69400113-T-G

Variant names:

Variant summary

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

The NM_133338.3(RAD17):c.1637T>G(p.Leu546Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,597,920 control chromosomes in the GnomAD database, including 77,290 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L546F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.25 ( 5668 hom., cov: 31)

Exomes 𝑓: 0.31 ( 71622 hom. )

Consequence

RAD17
NM_133338.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.45

Publications

39 publications found

Variant links:

Genes affected

RAD17 (HGNC:9807): (RAD17 checkpoint clamp loader component) The protein encoded by this gene is highly similar to the gene product of Schizosaccharomyces pombe rad17, a cell cycle checkpoint gene required for cell cycle arrest and DNA damage repair in response to DNA damage. This protein shares strong similarity with DNA replication factor C (RFC), and can form a complex with RFCs. This protein binds to chromatin prior to DNA damage and is phosphorylated by the checkpoint kinase ATR following damage. This protein recruits the RAD1-RAD9-HUS1 checkpoint protein complex onto chromatin after DNA damage, which may be required for its phosphorylation. The phosphorylation of this protein is required for the DNA-damage-induced cell cycle G2 arrest, and is thought to be a critical early event during checkpoint signaling in DNA-damaged cells. Multiple alternatively spliced transcript variants of this gene, which encode four distinct protein isoforms, have been reported. Two pseudogenes, located on chromosomes 7 and 13, have been identified. [provided by RefSeq, Jul 2013]

RAD17 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 (MetaRNN=0.0021357536).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAD17	NM_133338.3	MANE Select	c.1637T>G	p.Leu546Arg	missense	Exon 17 of 19	NP_579916.1
RAD17	NM_133339.2		c.1670T>G	p.Leu557Arg	missense	Exon 14 of 16	NP_579917.1
RAD17	NM_001278622.1		c.1637T>G	p.Leu546Arg	missense	Exon 16 of 18	NP_001265551.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAD17	ENST00000354868.10	TSL:1 MANE Select	c.1637T>G	p.Leu546Arg	missense	Exon 17 of 19	ENSP00000346938.5
RAD17	ENST00000380774.7	TSL:1	c.1670T>G	p.Leu557Arg	missense	Exon 14 of 16	ENSP00000370151.3
RAD17	ENST00000305138.8	TSL:1	c.1637T>G	p.Leu546Arg	missense	Exon 15 of 17	ENSP00000303134.4

Frequencies

GnomAD3 genomes

AF:

0.251

AC:

38000

AN:

151598

Hom.:

5664

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0772

Gnomad AMI

AF:

0.524

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.262

Gnomad EAS

AF:

0.312

Gnomad SAS

AF:

0.373

Gnomad FIN

AF:

0.318

Gnomad MID

AF:

0.261

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.252

GnomAD2 exomes

AF:

0.292

AC:

71463

AN:

244966

AF XY:

0.300

show subpopulations

Gnomad AFR exome

AF:

0.0686

Gnomad AMR exome

AF:

0.232

Gnomad ASJ exome

AF:

0.272

Gnomad EAS exome

AF:

0.302

Gnomad FIN exome

AF:

0.321

Gnomad NFE exome

AF:

0.317

Gnomad OTH exome

AF:

0.298

GnomAD4 exome

AF:

0.310

AC:

448794

AN:

1446206

Hom.:

71622

Cov.:

AF XY:

0.312

AC XY:

224674

AN XY:

719190

show subpopulations

African (AFR)

AF:

0.0701

AC:

2327

AN:

33180

American (AMR)

AF:

0.244

AC:

10640

AN:

43638

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

7086

AN:

25792

East Asian (EAS)

AF:

0.309

AC:

12092

AN:

39186

South Asian (SAS)

AF:

0.361

AC:

30142

AN:

83426

European-Finnish (FIN)

AF:

0.324

AC:

17106

AN:

52844

Middle Eastern (MID)

AF:

0.271

AC:

1120

AN:

4126

European-Non Finnish (NFE)

AF:

0.317

AC:

350381

AN:

1104536

Other (OTH)

AF:

0.301

AC:

17900

AN:

59478

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

13585

27169

40754

54338

67923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11424

22848

34272

45696

57120

<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:

0.250

AC:

38004

AN:

151714

Hom.:

5668

Cov.:

AF XY:

0.254

AC XY:

18848

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.0770

AC:

3196

AN:

41498

American (AMR)

AF:

0.284

AC:

4323

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

908

AN:

3470

East Asian (EAS)

AF:

0.312

AC:

1613

AN:

5168

South Asian (SAS)

AF:

0.373

AC:

1796

AN:

4814

European-Finnish (FIN)

AF:

0.318

AC:

3280

AN:

10308

Middle Eastern (MID)

AF:

0.257

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.321

AC:

21800

AN:

67918

Other (OTH)

AF:

0.255

AC:

535

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1372

2744

4116

5488

6860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.283

Hom.:

7946

Bravo

AF:

0.239

TwinsUK

AF:

0.313

AC:

1162

ALSPAC

AF:

0.334

AC:

1288

ESP6500AA

AF:

0.0840

AC:

370

ESP6500EA

AF:

0.322

AC:

2767

ExAC

AF:

0.299

AC:

36329

Asia WGS

AF:

0.329

AC:

1143

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

7.4

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.46

MPC

0.42

ClinPred

0.022

GERP RS

5.7

Varity_R

0.82

gMVP

0.93

Mutation Taster

=93/7

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

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