chr22-18167915-C-T

Position:

• chr22-18167915-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017414.4(USP18):​c.506C>T​(p.Thr169Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,612,966 control chromosomes in the GnomAD database, including 91,041 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.35 (9258 hom., cov: 29)
  • Exomes 𝑓: 0.33 (81783 hom.)
• Consequence: USP18 NM_017414.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.162

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.3164024E-4).
• BP6: Variant 22-18167915-C-T is Benign according to our data. Variant chr22-18167915-C-T is described in ClinVar as [Benign]. Clinvar id is 2628216.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP18	NM_017414.4	c.506C>T	p.Thr169Met	missense_variant	6/11	ENST00000215794.8
USP18	XM_006724074.4	c.284C>T	p.Thr95Met	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP18	ENST00000215794.8	c.506C>T	p.Thr169Met	missense_variant	6/11	1	NM_017414.4	P1
USP18	ENST00000699060.1	c.506C>T	p.Thr169Met	missense_variant	6/10
USP18	ENST00000699061.1	n.252C>T		non_coding_transcript_exon_variant	3/6

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52541 AN: 151300 Hom.: 9247 Cov.: 29

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.308

GnomAD3 exomes AF: 0.319 AC: 80090 AN: 251378 Hom.: 13213 AF XY: 0.318 AC XY: 43239 AN XY: 135868

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.332 AC: 484688 AN: 1461550 Hom.: 81783 Cov.: 40 AF XY: 0.331 AC XY: 240620 AN XY: 727106

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.324

GnomAD4 genome AF: 0.347 AC: 52589 AN: 151416 Hom.: 9258 Cov.: 29 AF XY: 0.344 AC XY: 25423 AN XY: 73970

Gnomad4 AFR AF: 0.389

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.161

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.346

Gnomad4 OTH AF: 0.307

Alfa AF: 0.356 Hom.: 5359

Bravo AF: 0.347

ESP6500AA AF: 0.388 AC: 1709

ESP6500EA AF: 0.345 AC: 2965

ExAC AF: 0.320 AC: 38892

Asia WGS AF: 0.227 AC: 789 AN: 3476

EpiCase AF: 0.337

EpiControl AF: 0.333

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.6
DANN	Benign	0.82
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.00033	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.038
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.57	P
Vest4		0.041
MPC		0.56
ClinPred		0.0043	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.028
gMVP		0.33

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: rs3180408; hg19: chr22-18650682; COSMIC: COSV53172792;