NM_020165.4:c.905G>A

Variant names:

• chr3-8913705-C-T
• rs373572
• NM_020165.4:c.905G>A

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25
• Publications: 54 publications found

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020165.4. 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
	RAD18	NM_020165.4	MANE Select	c.905G>A	p.Arg302Gln	missense	Exon 8 of 13	NP_064550.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD18	ENST00000264926.7	TSL:1 MANE Select	c.905G>A	p.Arg302Gln	missense	Exon 8 of 13	ENSP00000264926.2	Q9NS91
	RAD18	ENST00000956589.1		c.761G>A	p.Arg254Gln	missense	Exon 6 of 11	ENSP00000626648.1
	RAD18	ENST00000858877.1		c.244-1333G>A		intron	N/A	ENSP00000528936.1

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106180 AN: 152034 Hom.: 37556 Cov.: 32

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

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.: 32 AF XY: 0.716 AC XY: 502194 AN XY: 701334

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

GnomAD4 genome AF: 0.698 AC: 106260 AN: 152152 Hom.: 37581 Cov.: 32 AF XY: 0.698 AC XY: 51943 AN XY: 74390

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	21
DANN	Benign	0.64
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N
PhyloP100		2.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.15
Sift	Benign	0.62	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.020
MPC		0.053
ClinPred		0.70	D
GERP RS		4.5
Varity_R		0.042
gMVP		0.034
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs373572; hg19: chr3-8955389; COSMIC: COSV53750691; COSMIC: COSV53750691;