22-18167920-C-G

Variant names:

• chr22-18167920-C-G
• NM_017414.4:c.511C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017414.4(USP18):​c.511C>G​(p.Arg171Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP18 NM_017414.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.549

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09805226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP18	NM_017414.4	c.511C>G	p.Arg171Gly	missense_variant	Exon 6 of 11	ENST00000215794.8	NP_059110.2
USP18	XM_006724074.4	c.289C>G	p.Arg97Gly	missense_variant	Exon 5 of 10		XP_006724137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP18	ENST00000215794.8	c.511C>G	p.Arg171Gly	missense_variant	Exon 6 of 11	1	NM_017414.4	ENSP00000215794.7
USP18	ENST00000699060.1	c.511C>G	p.Arg171Gly	missense_variant	Exon 6 of 10			ENSP00000514107.1
USP18	ENST00000699061.1	n.257C>G		non_coding_transcript_exon_variant	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

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: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.2
DANN	Benign	0.80
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.024
Sift	Benign	0.12	T
Sift4G	Benign	0.37	T
Polyphen		0.0040	B
Vest4		0.092
MutPred		0.60		Gain of catalytic residue at V172 (P = 0.0183);
MVP		0.22
MPC		0.60
ClinPred		0.17	T
GERP RS		0.41
Varity_R		0.10
gMVP		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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-18650687;