chr22-18169868-C-T

Position:

• chr22-18169868-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017414.4(USP18):​c.652C>T​(p.Gln218Ter) 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

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 Pathogenic. Variant got 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 id is 417774.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP18	NM_017414.4	c.652C>T	p.Gln218Ter	stop_gained	7/11	ENST00000215794.8	NP_059110.2
USP18	XM_006724074.4	c.430C>T	p.Gln144Ter	stop_gained	6/10		XP_006724137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP18	ENST00000215794.8	c.652C>T	p.Gln218Ter	stop_gained	7/11	1	NM_017414.4	ENSP00000215794	P1
USP18	ENST00000699060.1	c.652C>T	p.Gln218Ter	stop_gained	7/10			ENSP00000514107
USP18	ENST00000699061.1	n.398C>T		non_coding_transcript_exon_variant	4/6

Frequencies

GnomAD3 genomes Cov.: 30

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pseudo-TORCH syndrome 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous p.Gln218Ter variant in USP18 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 417775), in two siblings with pseudo-TORCH syndrome 2 (PMID: 27325888). Familial exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 417775). These individuals along with 3 homozygous affected siblings from another family, were reported in the literature (PMID: 27325888). Of these 5 affected individuals (PMID: 27325888), 3 were homozygotes and 2 were compound heterozygotes who carried a likely pathogenic variant (ClinVar Variation ID: 417775) in trans, which increases the likelihood that the p.Gln218Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 417774) and has been interpreted as pathogenic by OMIM. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 218, which is predicted to lead to a truncated or absent protein. Loss of function of the USP18 gene is strongly associated to autosomal recessive pseudo-TORCH syndrome 2 (PMID: 27325888). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive pseudo-TORCH syndrome 2. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3, PP1 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 26, 2017	- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A
Vest4		0.75
GERP RS		5.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307118; hg19: chr22-18652635;