Genetic Variant RAD18:p.Arg302Gln (chr3-8913705-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020165.4(RAD18):c.905G>A(p.Arg302Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,561,528 control chromosomes in the GnomAD database, including 400,616 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. R302G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.70 ( 37581 hom., cov: 32)

Exomes 𝑓: 0.71 ( 363035 hom. )

Consequence

RAD18
NM_020165.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.25

Publications

54 publications found

Variant links:

Genes affected

RAD18 (HGNC:18278): (RAD18 E3 ubiquitin protein ligase) The protein encoded by this gene is highly similar to S. cerevisiae DNA damage repair protein Rad18. Yeast Rad18 functions through its interaction with Rad6, which is an ubiquitin-conjugating enzyme required for post-replication repair of damaged DNA. Similar to its yeast counterpart, this protein is able to interact with the human homolog of yeast Rad6 protein through a conserved ring-finger motif. Mutation of this motif results in defective replication of UV-damaged DNA and hypersensitivity to multiple mutagens. [provided by RefSeq, Jul 2008]

RAD18 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=1.0643613E-6).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD18	NM_020165.4 link	c.905G>A	p.Arg302Gln	missense_variant	Exon 8 of 13	ENST00000264926.7	NP_064550.3
RAD18	XM_017006873.2 link	c.647G>A	p.Arg216Gln	missense_variant	Exon 6 of 11		XP_016862362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD18	ENST00000264926.7 link	c.905G>A	p.Arg302Gln	missense_variant	Exon 8 of 13	1	NM_020165.4	ENSP00000264926.2		Q9NS91
RAD18	ENST00000415439.5 link	n.890-1333G>A		intron_variant	Intron 7 of 11	5		ENSP00000402049.1		F8WE49

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

106180

AN:

152034

Hom.:

37556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.666

Gnomad AMI

AF:

0.817

Gnomad AMR

AF:

0.694

Gnomad ASJ

AF:

0.721

Gnomad EAS

AF:

0.352

Gnomad SAS

AF:

0.734

Gnomad FIN

AF:

0.761

Gnomad MID

AF:

0.763

Gnomad NFE

AF:

0.730

Gnomad OTH

AF:

0.706

GnomAD2 exomes

AF:

0.682

AC:

151990

AN:

222744

AF XY:

0.693

show subpopulations

Gnomad AFR exome

AF:

0.656

Gnomad AMR exome

AF:

0.623

Gnomad ASJ exome

AF:

0.718

Gnomad EAS exome

AF:

0.334

Gnomad FIN exome

AF:

0.765

Gnomad NFE exome

AF:

0.725

Gnomad OTH exome

AF:

0.704

GnomAD4 exome

AF:

0.714

AC:

1006744

AN:

1409376

Hom.:

363035

Cov.:

AF XY:

0.716

AC XY:

502194

AN XY:

701334

show subpopulations

African (AFR)

AF:

0.653

AC:

20395

AN:

31224

American (AMR)

AF:

0.637

AC:

23999

AN:

37668

Ashkenazi Jewish (ASJ)

AF:

0.724

AC:

17893

AN:

24706

East Asian (EAS)

AF:

0.377

AC:

14651

AN:

38860

South Asian (SAS)

AF:

0.742

AC:

58601

AN:

79024

European-Finnish (FIN)

AF:

0.763

AC:

40224

AN:

52728

Middle Eastern (MID)

AF:

0.790

AC:

4432

AN:

5610

European-Non Finnish (NFE)

AF:

0.727

AC:

785662

AN:

1081118

Other (OTH)

AF:

0.700

AC:

40887

AN:

58438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

12596

25192

37788

50384

62980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19264

38528

57792

77056

96320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.698

AC:

106260

AN:

152152

Hom.:

37581

Cov.:

AF XY:

0.698

AC XY:

51943

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.666

AC:

27648

AN:

41520

American (AMR)

AF:

0.694

AC:

10611

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.721

AC:

2501

AN:

3470

East Asian (EAS)

AF:

0.352

AC:

1815

AN:

5160

South Asian (SAS)

AF:

0.734

AC:

3536

AN:

4818

European-Finnish (FIN)

AF:

0.761

AC:

8049

AN:

10580

Middle Eastern (MID)

AF:

0.762

AC:

224

AN:

294

European-Non Finnish (NFE)

AF:

0.730

AC:

49640

AN:

67998

Other (OTH)

AF:

0.707

AC:

1491

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1620

3240

4859

6479

8099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

818

1636

2454

3272

4090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.714

Hom.:

130349

Bravo

AF:

0.690

TwinsUK

AF:

0.716

AC:

2656

ALSPAC

AF:

0.732

AC:

2823

ESP6500AA

AF:

0.666

AC:

2931

ESP6500EA

AF:

0.724

AC:

6219

ExAC

AF:

0.691

AC:

83707

Asia WGS

AF:

0.553

AC:

1922

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.088

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0000011

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.6

PhyloP100

2.2

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.25

REVEL

Benign

0.15

Sift

Benign

0.62

Sift4G

Benign

0.38

Polyphen

0.0010

Vest4

0.020

MPC

0.053

ClinPred

0.70

GERP RS

4.5

Varity_R

0.042

gMVP

0.034

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over