Genetic Variant RAD18:p.Asn320His (chr3-8913652-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020165.4(RAD18):c.958A>C(p.Asn320His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,404,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N320T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

RAD18
NM_020165.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29576284).

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.958A>C	p.Asn320His	missense	Exon 8 of 13	NP_064550.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAD18	ENST00000264926.7	TSL:1 MANE Select	c.958A>C	p.Asn320His	missense	Exon 8 of 13	ENSP00000264926.2	Q9NS91
RAD18	ENST00000956589.1		c.814A>C	p.Asn272His	missense	Exon 6 of 11	ENSP00000626648.1
RAD18	ENST00000858877.1		c.244-1280A>C		intron	N/A	ENSP00000528936.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000456

AC:

AN:

219082

AF XY:

0.00

show subpopulations

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:

0.00000958

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000285

AC:

AN:

1404600

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30778

American (AMR)

AF:

0.00

AC:

AN:

36222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24632

East Asian (EAS)

AF:

0.00

AC:

AN:

38486

South Asian (SAS)

AF:

0.00

AC:

AN:

78300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5604

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1079608

Other (OTH)

AF:

0.0000172

AC:

AN:

58180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.77

M_CAP

Benign

0.0060

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

2.2

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

REVEL

Benign

0.042

Sift

Benign

0.089

Sift4G

Benign

0.069

Polyphen

0.94

Vest4

0.48

MutPred

0.17

Gain of glycosylation at S322 (P = 0.0316)

MVP

0.18

MPC

0.22

ClinPred

0.75

GERP RS

4.5

Varity_R

0.12

gMVP

0.046

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over