chr22-18167915-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.35 ( 9258 hom., cov: 29)

Exomes 𝑓: 0.33 ( 81783 hom. )

Consequence

USP18
NM_017414.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.162

Publications

30 publications found

Variant links:

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

USP18 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

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.506C>T	p.Thr169Met	missense	Exon 6 of 11	NP_059110.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP18	ENST00000215794.8	TSL:1 MANE Select	c.506C>T	p.Thr169Met	missense	Exon 6 of 11	ENSP00000215794.7	Q9UMW8-1
USP18	ENST00000896324.1		c.530C>T	p.Thr177Met	missense	Exon 6 of 11	ENSP00000566383.1
USP18	ENST00000896317.1		c.506C>T	p.Thr169Met	missense	Exon 6 of 11	ENSP00000566376.1

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52541

AN:

151300

Hom.:

9247

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.319

AC:

80090

AN:

251378

AF XY:

0.318

show subpopulations

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 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.:

AF XY:

0.331

AC XY:

240620

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.387

AC:

12945

AN:

33462

American (AMR)

AF:

0.297

AC:

13285

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

8434

AN:

26130

East Asian (EAS)

AF:

0.163

AC:

6451

AN:

39692

South Asian (SAS)

AF:

0.309

AC:

26637

AN:

86246

European-Finnish (FIN)

AF:

0.325

AC:

17374

AN:

53414

Middle Eastern (MID)

AF:

0.304

AC:

1751

AN:

5768

European-Non Finnish (NFE)

AF:

0.340

AC:

378272

AN:

1111748

Other (OTH)

AF:

0.324

AC:

19539

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

18517

37034

55552

74069

92586

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12042

24084

36126

48168

60210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.347

AC:

52589

AN:

151416

Hom.:

9258

Cov.:

AF XY:

0.344

AC XY:

25423

AN XY:

73970

show subpopulations

African (AFR)

AF:

0.389

AC:

16026

AN:

41216

American (AMR)

AF:

0.337

AC:

5138

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

1093

AN:

3458

East Asian (EAS)

AF:

0.161

AC:

830

AN:

5144

South Asian (SAS)

AF:

0.317

AC:

1514

AN:

4776

European-Finnish (FIN)

AF:

0.309

AC:

3233

AN:

10466

Middle Eastern (MID)

AF:

0.325

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.346

AC:

23473

AN:

67830

Other (OTH)

AF:

0.307

AC:

644

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1627

3255

4882

6510

8137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

500

1000

1500

2000

2500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.351

Hom.:

6743

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.6

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.11

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.36

MetaRNN

Benign

0.00033

MetaSVM

Benign

-0.96

PhyloP100

-0.16

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.0

REVEL

Benign

0.038

Sift

Benign

0.19

Sift4G

Benign

0.21

Polyphen

0.57

Vest4

0.041

MPC

0.56

ClinPred

0.0043

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.33

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over