chr3-8939636-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_020165.4(RAD18):c.622G>A(p.Gly208Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,611,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
RAD18
NM_020165.4 missense
NM_020165.4 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 1.48
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD18 | NM_020165.4 | c.622G>A | p.Gly208Arg | missense_variant | 6/13 | ENST00000264926.7 | |
RAD18 | XM_017006873.2 | c.364G>A | p.Gly122Arg | missense_variant | 4/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD18 | ENST00000264926.7 | c.622G>A | p.Gly208Arg | missense_variant | 6/13 | 1 | NM_020165.4 | P1 | |
RAD18 | ENST00000415439.5 | c.622G>A | p.Gly208Arg | missense_variant, NMD_transcript_variant | 6/12 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152034Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000519 AC: 13AN: 250324Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135298
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GnomAD4 exome AF: 0.0000370 AC: 54AN: 1459776Hom.: 0 Cov.: 30 AF XY: 0.0000482 AC XY: 35AN XY: 726252
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GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152034Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74240
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2022 | The c.622G>A (p.G208R) alteration is located in exon 6 (coding exon 6) of the RAD18 gene. This alteration results from a G to A substitution at nucleotide position 622, causing the glycine (G) at amino acid position 208 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of MoRF binding (P = 0.0843);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at