rs5992185

Positions:

• chr22-18151211-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017414.4(USP18):​c.-107+989A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 151,846 control chromosomes in the GnomAD database, including 13,125 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 0.40 (13125 hom., cov: 32)
• Consequence: USP18 NM_017414.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350

Genes affected

USP18 (HGNC:12616): (ubiquitin specific peptidase 18) The protein encoded by this gene belongs to the ubiquitin-specific proteases (UBP) family of enzymes that cleave ubiquitin from ubiquitinated protein substrates. It is highly expressed in liver and thymus, and is localized to the nucleus. This protein efficiently cleaves only ISG15 (a ubiquitin-like protein) fusions, and deletion of this gene in mice results in a massive increase of ISG15 conjugates in tissues, indicating that this protein is a major ISG15-specific protease. Mice lacking this gene are also hypersensitive to interferon, suggesting a function of this protein in downregulating interferon responses, independent of its isopeptidase activity towards ISG15. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP18	NM_017414.4	c.-107+989A>C		intron_variant		ENST00000215794.8	NP_059110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP18	ENST00000215794.8	c.-107+989A>C		intron_variant		1	NM_017414.4	ENSP00000215794	P1
USP18	ENST00000699060.1	c.-107+989A>C		intron_variant				ENSP00000514107

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60347 AN: 151728 Hom.: 13105 Cov.: 32

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.0545

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.369

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

GnomAD4 genome AF: 0.398 AC: 60418 AN: 151846 Hom.: 13125 Cov.: 32 AF XY: 0.393 AC XY: 29140 AN XY: 74216

Gnomad4 AFR AF: 0.566

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.376

Gnomad4 EAS AF: 0.0544

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.365

Alfa AF: 0.357 Hom.: 20513

Bravo AF: 0.402

Asia WGS AF: 0.163 AC: 571 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.9
DANN	Benign	0.42

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

LitVar

Other links and lift over

dbSNP: rs5992185; hg19: chr22-18633978;