22-18161890-C-G

Variant names:

• chr22-18161890-C-G
• rs187908474
• NM_017414.4:c.355C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017414.4(USP18):​c.355C>G​(p.Arg119Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R119Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: USP18 NM_017414.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• Publications: 2 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, Labcorp Genetics (formerly Invitae), Orphanet, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21268883).

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.355C>G	p.Arg119Gly	missense	Exon 4 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.355C>G	p.Arg119Gly	missense	Exon 4 of 11	ENSP00000215794.7	Q9UMW8-1
	USP18	ENST00000896324.1		c.379C>G	p.Arg127Gly	missense	Exon 4 of 11	ENSP00000566383.1
	USP18	ENST00000896317.1		c.355C>G	p.Arg119Gly	missense	Exon 4 of 11	ENSP00000566376.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152118 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251240 AF XY: 0.0000368

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: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461770 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111952

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152118 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000741 AC: 9

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.23
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.084
Sift	Benign	0.37	T
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.50		Gain of ubiquitination at K116 (P = 0.0445)
MVP		0.24
MPC		0.59
ClinPred		0.058	T
GERP RS		3.1
Varity_R		0.10
gMVP		0.29
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs187908474; hg19: chr22-18644657;