rs1060499892

Variant names:

• chr5-69400069-A-G
• rs1060499892
• NM_133338.3:c.1593A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_133338.3(RAD17):​c.1593A>G​(p.Ala531Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD17 NM_133338.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.463
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-69400069-A-G is Benign according to our data. Variant chr5-69400069-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 403359.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.463 with no splicing effect.

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.1593A>G	p.Ala531Ala	synonymous	Exon 17 of 19	NP_579916.1	O75943-2
	RAD17	NM_133339.2		c.1626A>G	p.Ala542Ala	synonymous	Exon 14 of 16	NP_579917.1	O75943-1
	RAD17	NM_001278622.1		c.1593A>G	p.Ala531Ala	synonymous	Exon 16 of 18	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.1593A>G	p.Ala531Ala	synonymous	Exon 17 of 19	ENSP00000346938.5	O75943-2
	RAD17	ENST00000380774.7	TSL:1	c.1626A>G	p.Ala542Ala	synonymous	Exon 14 of 16	ENSP00000370151.3	O75943-1
	RAD17	ENST00000305138.8	TSL:1	c.1593A>G	p.Ala531Ala	synonymous	Exon 15 of 17	ENSP00000303134.4	O75943-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.7
DANN	Benign	0.55
PhyloP100		0.46

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: rs1060499892; hg19: chr5-68695896;