3-8936035-G-T

Variant names:

• chr3-8936035-G-T
• rs200605306
• NM_020165.4:c.725C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020165.4(RAD18):​c.725C>A​(p.Pro242Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P242L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAD18 NM_020165.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20321855).

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.725C>A	p.Pro242Gln	missense	Exon 7 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.725C>A	p.Pro242Gln	missense	Exon 7 of 13	ENSP00000264926.2	Q9NS91
	RAD18	ENST00000956589.1		c.581C>A	p.Pro194Gln	missense	Exon 5 of 11	ENSP00000626648.1
	RAD18	ENST00000858877.1		c.243+11208C>A		intron	N/A	ENSP00000528936.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438590 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 715250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31944

American (AMR) AF: 0.00 AC: 0 AN: 40198

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 39156

South Asian (SAS) AF: 0.00 AC: 0 AN: 81738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102338

Other (OTH) AF: 0.00 AC: 0 AN: 59308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.029
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.6
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.061
Sift	Benign	0.075	T
Sift4G	Uncertain	0.028	D
Polyphen		0.14	B
Vest4		0.40
MutPred		0.23		Loss of glycosylation at P244 (P = 0.0219)
MVP		0.25
MPC		0.092
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.24
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200605306; hg19: chr3-8977719;