rs1045051

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-69400113-T-A
• chr5-69400113-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_133338.3(RAD17):​c.1637T>A​(p.Leu546His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,449,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RAD17 NM_133338.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.45
• Publications: 39 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

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.1637T>A	p.Leu546His	missense	Exon 17 of 19	NP_579916.1	O75943-2
	RAD17	NM_133339.2		c.1670T>A	p.Leu557His	missense	Exon 14 of 16	NP_579917.1	O75943-1
	RAD17	NM_001278622.1		c.1637T>A	p.Leu546His	missense	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.1637T>A	p.Leu546His	missense	Exon 17 of 19	ENSP00000346938.5	O75943-2
	RAD17	ENST00000380774.7	TSL:1	c.1670T>A	p.Leu557His	missense	Exon 14 of 16	ENSP00000370151.3	O75943-1
	RAD17	ENST00000305138.8	TSL:1	c.1637T>A	p.Leu546His	missense	Exon 15 of 17	ENSP00000303134.4	O75943-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000816 AC: 2 AN: 244966 AF XY: 0.0000151

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1449178 Hom.: 0 Cov.: 33 AF XY: 0.00000555 AC XY: 4 AN XY: 720782

African (AFR) AF: 0.0000301 AC: 1 AN: 33224

American (AMR) AF: 0.00 AC: 0 AN: 43894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39320

South Asian (SAS) AF: 0.00 AC: 0 AN: 84170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1105976

Other (OTH) AF: 0.00 AC: 0 AN: 59632

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.63		Gain of helix (P = 0.0325)
MVP		0.75
MPC		0.40
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.76
gMVP		0.82
Mutation Taster		=60/40	polymorphism

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: rs1045051; hg19: chr5-68695940;