3-8913705-C-T

Position:

• chr3-8913705-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
RAD18	NM_020165.4	c.905G>A	p.Arg302Gln	missense_variant	8/13	ENST00000264926.7	NP_064550.3
RAD18	XM_017006873.2	c.647G>A	p.Arg216Gln	missense_variant	6/11		XP_016862362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD18	ENST00000264926.7	c.905G>A	p.Arg302Gln	missense_variant	8/13	1	NM_020165.4	ENSP00000264926.2
RAD18	ENST00000415439.5	n.890-1333G>A		intron_variant		5		ENSP00000402049.1

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

GnomAD3 exomes AF: 0.682 AC: 151990 AN: 222744 Hom.: 53307 AF XY: 0.693 AC XY: 83537 AN XY: 120558

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 SAS exome AF: 0.733

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

Gnomad4 AFR exome AF: 0.653

Gnomad4 AMR exome AF: 0.637

Gnomad4 ASJ exome AF: 0.724

Gnomad4 EAS exome AF: 0.377

Gnomad4 SAS exome AF: 0.742

Gnomad4 FIN exome AF: 0.763

Gnomad4 NFE exome AF: 0.727

Gnomad4 OTH exome AF: 0.700

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

Gnomad4 AFR AF: 0.666

Gnomad4 AMR AF: 0.694

Gnomad4 ASJ AF: 0.721

Gnomad4 EAS AF: 0.352

Gnomad4 SAS AF: 0.734

Gnomad4 FIN AF: 0.761

Gnomad4 NFE AF: 0.730

Gnomad4 OTH AF: 0.707

Alfa AF: 0.719 Hom.: 96454

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	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
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

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

LitVar

Other links and lift over

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