Variant 5-69400113-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000354868.10(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
ENST00000354868.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.45

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 made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD17	NM_133338.3 linkuse as main transcript	c.1637T>G	p.Leu546Arg	missense_variant	17/19	ENST00000354868.10	NP_579916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD17	ENST00000354868.10 linkuse as main transcript	c.1637T>G	p.Leu546Arg	missense_variant	17/19	1	NM_133338.3	ENSP00000346938		O75943-2

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

GnomAD3 exomes

AF:

0.292

AC:

71463

AN:

244966

Hom.:

11118

AF XY:

0.300

AC XY:

39861

AN XY:

132696

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 SAS exome

AF:

0.363

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

Gnomad4 AFR exome

AF:

0.0701

Gnomad4 AMR exome

AF:

0.244

Gnomad4 ASJ exome

AF:

0.275

Gnomad4 EAS exome

AF:

0.309

Gnomad4 SAS exome

AF:

0.361

Gnomad4 FIN exome

AF:

0.324

Gnomad4 NFE exome

AF:

0.317

Gnomad4 OTH exome

AF:

0.301

GnomAD4 genome

AF:

0.250

AC:

38004

AN:

151714

Hom.:

5668

Cov.:

AF XY:

0.254

AC XY:

18848

AN XY:

74142

show subpopulations

Gnomad4 AFR

AF:

0.0770

Gnomad4 AMR

AF:

0.284

Gnomad4 ASJ

AF:

0.262

Gnomad4 EAS

AF:

0.312

Gnomad4 SAS

AF:

0.373

Gnomad4 FIN

AF:

0.318

Gnomad4 NFE

AF:

0.321

Gnomad4 OTH

AF:

0.255

Alfa

AF:

0.293

Hom.:

4727

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;T;.;.;.;.;.;.;.;.;T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

.;.;.;.;.;.;T;.;T;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

.;M;.;.;.;.;.;.;.;.;M;.

MutationTaster

Benign

7.4e-8

P;P;P;P;P;P;P;P;P;P

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.8

D;D;D;D;D;D;.;D;D;D;D;D

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

D;D;D;D;D;D;.;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;D;D;D;D;D;.;D;.

Vest4

0.46

MPC

0.42

ClinPred

0.022

GERP RS

5.7

Varity_R

0.82

gMVP

0.93

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over