chr22-18157698-G-A

Position:

• chr22-18157698-G-A

Variant summary

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

The NM_017414.4(USP18):​c.35G>A​(p.Cys12Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP18 NM_017414.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.328

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=0.08165449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP18	NM_017414.4	c.35G>A	p.Cys12Tyr	missense_variant	2/11	ENST00000215794.8	NP_059110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP18	ENST00000215794.8	c.35G>A	p.Cys12Tyr	missense_variant	2/11	1	NM_017414.4	ENSP00000215794.7
USP18	ENST00000699060.1	c.35G>A	p.Cys12Tyr	missense_variant	2/10			ENSP00000514107.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2024

The c.35G>A (p.C12Y) alteration is located in exon 2 (coding exon 1) of the USP18 gene. This alteration results from a G to A substitution at nucleotide position 35, causing the cysteine (C) at amino acid position 12 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.97	L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.037
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.23
MutPred		0.40		Gain of helix (P = 0.0225);
MVP		0.16
MPC		1.3
ClinPred		0.16	T
GERP RS		0.43
Varity_R		0.070
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs1407463503; hg19: chr22-18640465;