rs75775

Variant names:

• chr3-8779046-T-G
• rs75775
• ENST00000427329.5:c.294-3382A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000427329.5(RAD18):​c.294-3382A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.851 in 152,060 control chromosomes in the GnomAD database, including 55,582 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.85 (55582 hom., cov: 32)
• Consequence: RAD18 ENST00000427329.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.541

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]

CAV3 (HGNC:1529): (caveolin 3) This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules. Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia or rippling muscle disease (RMD). Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD18	ENST00000427329.5	c.294-3382A>C		intron_variant	Intron 3 of 3	3		ENSP00000412054.1
CAV3	ENST00000472766.1	n.215+1510T>G		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.851 AC: 129332 AN: 151942 Hom.: 55528 Cov.: 32

Gnomad AFR AF: 0.926

Gnomad AMI AF: 0.893

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.870

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.851 AC: 129443 AN: 152060 Hom.: 55582 Cov.: 32 AF XY: 0.845 AC XY: 62784 AN XY: 74332

Gnomad4 AFR AF: 0.926 AC: 0.925994 AN: 0.925994

Gnomad4 AMR AF: 0.779 AC: 0.779406 AN: 0.779406

Gnomad4 ASJ AF: 0.870 AC: 0.870104 AN: 0.870104

Gnomad4 EAS AF: 0.616 AC: 0.615891 AN: 0.615891

Gnomad4 SAS AF: 0.870 AC: 0.870493 AN: 0.870493

Gnomad4 FIN AF: 0.727 AC: 0.727023 AN: 0.727023

Gnomad4 NFE AF: 0.855 AC: 0.855262 AN: 0.855262

Gnomad4 OTH AF: 0.870 AC: 0.869915 AN: 0.869915

Alfa AF: 0.859 Hom.: 175467

Bravo AF: 0.857

Asia WGS AF: 0.751 AC: 2614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.7
DANN	Benign	0.84

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75775; hg19: chr3-8820732;