dbSNP rs373572: RAD18:p.Arg302Leu (chr3-8913705-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020165.4(RAD18):c.905G>T(p.Arg302Leu) 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. 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: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD18	NM_020165.4 link	c.905G>T	p.Arg302Leu	missense_variant	Exon 8 of 13	ENST00000264926.7	NP_064550.3
RAD18	XM_017006873.2 link	c.647G>T	p.Arg216Leu	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>T	p.Arg302Leu	missense_variant	Exon 8 of 13	1	NM_020165.4	ENSP00000264926.2		Q9NS91
RAD18	ENST00000415439.5 link	n.890-1333G>T		intron_variant	Intron 7 of 11	5		ENSP00000402049.1		F8WE49

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1414110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703674

African (AFR)

AF:

0.00

AC:

AN:

31352

American (AMR)

AF:

0.00

AC:

AN:

38006

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24824

East Asian (EAS)

AF:

0.00

AC:

AN:

38972

South Asian (SAS)

AF:

0.00

AC:

AN:

79402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5624

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084512

Other (OTH)

AF:

0.00

AC:

AN:

58594

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.42

M_CAP

Benign

0.011

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

2.2

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.075

Sift

Uncertain

0.012

Sift4G

Uncertain

0.032

Polyphen

0.086

Vest4

0.16

MutPred

0.33

Loss of MoRF binding (P = 0.0386);

MVP

0.21

MPC

0.061

ClinPred

0.96

GERP RS

4.5

Varity_R

0.18

gMVP

0.067

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.29

Position offset: 15

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over