chr5-69391863-A-G

Position:

chr5-69391863-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_133338.3(RAD17):c.1039A>G(p.Met347Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000734 in 1,567,780 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 3 hom. )

Consequence

RAD17
NM_133338.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.12

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056815445).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD17	NM_133338.3 linkuse as main transcript	c.1039A>G	p.Met347Val	missense_variant	13/19	ENST00000354868.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD17	ENST00000354868.10 linkuse as main transcript	c.1039A>G	p.Met347Val	missense_variant	13/19	1	NM_133338.3		O75943-2

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00101

AC:

212

AN:

210292

Hom.:

AF XY:

0.000991

AC XY:

114

AN XY:

115066

show subpopulations

Gnomad AFR exome

AF:

0.000140

Gnomad AMR exome

AF:

0.0000884

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000129

Gnomad FIN exome

AF:

0.00221

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.000830

GnomAD4 exome

AF:

0.000735

AC:

1040

AN:

1415572

Hom.:

Cov.:

AF XY:

0.000730

AC XY:

514

AN XY:

704234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000331

Gnomad4 AMR exome

AF:

0.000187

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000115

Gnomad4 FIN exome

AF:

0.00180

Gnomad4 NFE exome

AF:

0.000812

Gnomad4 OTH exome

AF:

0.000653

GnomAD4 genome

AF:

0.000723

AC:

110

AN:

152208

Hom.:

Cov.:

AF XY:

0.000807

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000808

Hom.:

Bravo

AF:

0.000442

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00123

AC:

150

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2024

The c.1072A>G (p.M358V) alteration is located in exon 10 (coding exon 10) of the RAD17 gene. This alteration results from a A to G substitution at nucleotide position 1072, causing the methionine (M) at amino acid position 358 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.0050

DANN

Benign

0.34

DEOGEN2

Benign

0.041

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.40

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

M_CAP

Benign

0.0048

MetaRNN

Benign

0.0057

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

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.69

.;N;.;.;.;.;.;.;.;.;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

0.030

N;N;N;N;N;N;.;N;N;N;N

REVEL

Benign

0.013

Sift

Benign

0.32

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

Sift4G

Benign

0.56

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

Polyphen

0.0

B;B;B;.;B;B;B;B;B;.;B

Vest4

0.045

MVP

0.27

MPC

0.055

ClinPred

0.0090

GERP RS

-4.7

Varity_R

0.038

gMVP

0.15

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over