chr5-69409377-T-A

Variant names:

• chr5-69409377-T-A
• rs1168405
• NM_133338.3:c.1694-1116T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133338.3(RAD17):​c.1694-1116T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 151,884 control chromosomes in the GnomAD database, including 18,834 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.

• Frequency: Genomes: 𝑓 0.50 (18834 hom., cov: 31)
• Consequence: RAD17 NM_133338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.524 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD17	NM_133338.3	MANE Select	c.1694-1116T>A		intron	N/A	NP_579916.1	O75943-2
	RAD17	NM_133339.2		c.1727-1116T>A		intron	N/A	NP_579917.1	O75943-1
	RAD17	NM_001278622.1		c.1694-1116T>A		intron	N/A	NP_001265551.1	O75943-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD17	ENST00000354868.10	TSL:1 MANE Select	c.1694-1116T>A		intron	N/A	ENSP00000346938.5	O75943-2
	RAD17	ENST00000380774.7	TSL:1	c.1727-1116T>A		intron	N/A	ENSP00000370151.3	O75943-1
	RAD17	ENST00000305138.8	TSL:1	c.1694-1116T>A		intron	N/A	ENSP00000303134.4	O75943-2

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75530 AN: 151766 Hom.: 18830 Cov.: 31

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.490

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75582 AN: 151884 Hom.: 18834 Cov.: 31 AF XY: 0.505 AC XY: 37443 AN XY: 74210

African (AFR) AF: 0.479 AC: 19850 AN: 41412

American (AMR) AF: 0.533 AC: 8133 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1756 AN: 3462

East Asian (EAS) AF: 0.494 AC: 2546 AN: 5152

South Asian (SAS) AF: 0.535 AC: 2575 AN: 4812

European-Finnish (FIN) AF: 0.585 AC: 6167 AN: 10548

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32872 AN: 67942

Other (OTH) AF: 0.494 AC: 1038 AN: 2102

Alfa AF: 0.497 Hom.: 2370

Bravo AF: 0.490

Asia WGS AF: 0.516 AC: 1795 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1168405; hg19: chr5-68705204; COSMIC: COSV51456946;