rs1085307118

Variant names:

• chr22-18169868-C-T
• rs1085307118
• NM_017414.4:c.652C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017414.4(USP18):​c.652C>T​(p.Gln218*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USP18 NM_017414.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.88
• Publications: 3 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-18169868-C-T is Pathogenic according to our data. Variant chr22-18169868-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 417774.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017414.4. 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
	USP18	NM_017414.4	MANE Select	c.652C>T	p.Gln218*	stop_gained	Exon 7 of 11	NP_059110.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP18	ENST00000215794.8	TSL:1 MANE Select	c.652C>T	p.Gln218*	stop_gained	Exon 7 of 11	ENSP00000215794.7
	USP18	ENST00000896324.1		c.676C>T	p.Gln226*	stop_gained	Exon 7 of 11	ENSP00000566383.1
	USP18	ENST00000896317.1		c.652C>T	p.Gln218*	stop_gained	Exon 7 of 11	ENSP00000566376.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00 AC: 0 AN: 233814 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1452348 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721344

African (AFR) AF: 0.00 AC: 0 AN: 33274

American (AMR) AF: 0.00 AC: 0 AN: 43814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.00 AC: 0 AN: 84146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107078

Other (OTH) AF: 0.00 AC: 0 AN: 60034

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Pseudo-TORCH syndrome 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		2.9
Vest4		0.75
GERP RS		5.4
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1085307118; hg19: chr22-18652635;