Variant 5-69386224-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_133338.3(RAD17):c.743C>T(p.Ser248Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,455,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

RAD17
NM_133338.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.23

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD17	NM_133338.3 linkuse as main transcript	c.743C>T	p.Ser248Leu	missense_variant	10/19	ENST00000354868.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD17	ENST00000354868.10 linkuse as main transcript	c.743C>T	p.Ser248Leu	missense_variant	10/19	1	NM_133338.3		O75943-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249902

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000756

AC:

AN:

1455896

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

723968

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000812

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

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

Apr 18, 2023

The c.776C>T (p.S259L) alteration is located in exon 7 (coding exon 7) of the RAD17 gene. This alteration results from a C to T substitution at nucleotide position 776, causing the serine (S) at amino acid position 259 to be replaced by a leucine (L). 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

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

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

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.96

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

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

3.7

.;H;.;.;.;.;.;.;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.8

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

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.95

MutPred

0.84

.;Gain of sheet (P = 0.0221);.;.;.;.;.;.;.;.;Gain of sheet (P = 0.0221);

MVP

0.82

MPC

0.34

ClinPred

0.99

GERP RS

5.2

Varity_R

0.85

gMVP

0.87

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