5-69400113-T-G

Variant names:

• chr5-69400113-T-G
• rs1045051
• NM_133338.3:c.1637T>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.45

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]

ACMG classification

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 rank	MANE	Protein	UniProt
RAD17	NM_133338.3	c.1637T>G	p.Leu546Arg	missense_variant	Exon 17 of 19	ENST00000354868.10	NP_579916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD17	ENST00000354868.10	c.1637T>G	p.Leu546Arg	missense_variant	Exon 17 of 19	1	NM_133338.3	ENSP00000346938.5

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38000 AN: 151598 Hom.: 5664 Cov.: 31

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

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.: 33 AF XY: 0.312 AC XY: 224674 AN XY: 719190

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.: 31 AF XY: 0.254 AC XY: 18848 AN XY: 74142

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	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
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	D
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	T
MutationAssessor	Uncertain	2.6	.;M;.;.;.;.;.;.;.;.;M;.
PrimateAI	Uncertain	0.76	T
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	T
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

Other links and lift over

dbSNP: rs1045051; hg19: chr5-68695940; COSMIC: COSV51456873;