rs2542109

Variant names:

• chr22-18167094-A-G
• rs2542109
• NM_017414.4:c.401-161A>G

Variant summary

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

The NM_017414.4(USP18):​c.401-161A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 151,986 control chromosomes in the GnomAD database, including 24,289 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 0.52 (24289 hom., cov: 30)
• Consequence: USP18 NM_017414.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0240
• Publications: 7 publications found

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]

USP18 Gene-Disease associations (from GenCC):

• pseudo-TORCH syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP18	NM_017414.4	c.401-161A>G		intron_variant	Intron 4 of 10	ENST00000215794.8	NP_059110.2
USP18	XM_006724074.4	c.179-161A>G		intron_variant	Intron 3 of 9		XP_006724137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP18	ENST00000215794.8	c.401-161A>G		intron_variant	Intron 4 of 10	1	NM_017414.4	ENSP00000215794.7
USP18	ENST00000699060.2	c.401-161A>G		intron_variant	Intron 4 of 9			ENSP00000514107.1
USP18	ENST00000699061.1	n.147-161A>G		intron_variant	Intron 1 of 5
USP18	ENST00000715585.1	n.*275-161A>G		intron_variant	Intron 4 of 10			ENSP00000520484.1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79331 AN: 151870 Hom.: 24215 Cov.: 30

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.473

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

GnomAD4 genome AF: 0.523 AC: 79471 AN: 151986 Hom.: 24289 Cov.: 30 AF XY: 0.523 AC XY: 38830 AN XY: 74288

African (AFR) AF: 0.845 AC: 35059 AN: 41470

American (AMR) AF: 0.538 AC: 8211 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1181 AN: 3468

East Asian (EAS) AF: 0.681 AC: 3517 AN: 5168

South Asian (SAS) AF: 0.449 AC: 2161 AN: 4812

European-Finnish (FIN) AF: 0.354 AC: 3738 AN: 10546

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.353 AC: 23959 AN: 67940

Other (OTH) AF: 0.472 AC: 996 AN: 2110

Alfa AF: 0.474 Hom.: 14336

Bravo AF: 0.551

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.47
PhyloP100		0.024
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2542109; hg19: chr22-18649861;