5-69381919-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_133338.3(RAD17):c.370A>G(p.Ile124Val) variant causes a missense 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. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD17 NM_133338.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.115

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD17	NM_133338.3	c.370A>G	p.Ile124Val	missense_variant	7/19	ENST00000354868.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD17	ENST00000354868.10	c.370A>G	p.Ile124Val	missense_variant	7/19	1	NM_133338.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.403A>G (p.I135V) alteration is located in exon 4 (coding exon 4) of the RAD17 gene. This alteration results from a A to G substitution at nucleotide position 403, causing the isoleucine (I) at amino acid position 135 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	0.083
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.96	N;N;N;N;N;.;N;N;N;N
REVEL	Benign	0.049
Sift	Uncertain	0.013	D;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D;D;D;D
Polyphen		0.061	B;B;B;B;B;B;.;B;B;B
Vest4		0.33
MutPred		0.60		.;Loss of sheet (P = 0.1501);.;.;.;.;.;.;.;Loss of sheet (P = 0.1501);
MVP		0.22
MPC		0.049
ClinPred		0.67	D
GERP RS		0.93
Varity_R		0.046
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-68677746;