Genetic Variant USP18:c.401-100A>G (chr22-18167155-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_017414.4(USP18):c.401-100A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,409,008 control chromosomes in the GnomAD database, including 87,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.40 ( 13509 hom., cov: 30)

Exomes 𝑓: 0.34 ( 73940 hom. )

Consequence

USP18
NM_017414.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.494

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 22-18167155-A-G is Benign according to our data. Variant chr22-18167155-A-G is described in ClinVar as [Benign]. Clinvar id is 2688152.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP18	NM_017414.4 link	c.401-100A>G		intron_variant	Intron 4 of 10	ENST00000215794.8	NP_059110.2	Q9UMW8-1
USP18	XM_006724074.4 link	c.179-100A>G		intron_variant	Intron 3 of 9		XP_006724137.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP18	ENST00000215794.8 link	c.401-100A>G	intron_variant	Intron 4 of 10	1	NM_017414.4	ENSP00000215794.7	Q9UMW8-1
USP18	ENST00000699060.1 link	c.401-100A>G	intron_variant	Intron 4 of 9			ENSP00000514107.1	A0A8V8TMN0
USP18	ENST00000699061.1 link	n.147-100A>G	intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61371

AN:

151868

Hom.:

13465

Cov.:

show subpopulations

Gnomad AFR

AF:

0.586

Gnomad AMI

AF:

0.597

Gnomad AMR

AF:

0.358

Gnomad ASJ

AF:

0.318

Gnomad EAS

AF:

0.161

Gnomad SAS

AF:

0.319

Gnomad FIN

AF:

0.308

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.347

Gnomad OTH

AF:

0.363

GnomAD4 exome

AF:

0.337

AC:

423565

AN:

1257022

Hom.:

73940

AF XY:

0.335

AC XY:

209380

AN XY:

624352

show subpopulations

Gnomad4 AFR exome

AF:

0.596

Gnomad4 AMR exome

AF:

0.310

Gnomad4 ASJ exome

AF:

0.322

Gnomad4 EAS exome

AF:

0.161

Gnomad4 SAS exome

AF:

0.309

Gnomad4 FIN exome

AF:

0.325

Gnomad4 NFE exome

AF:

0.340

Gnomad4 OTH exome

AF:

0.337

GnomAD4 genome

AF:

0.405

AC:

61479

AN:

151986

Hom.:

13509

Cov.:

AF XY:

0.399

AC XY:

29644

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.586

Gnomad4 AMR

AF:

0.358

Gnomad4 ASJ

AF:

0.318

Gnomad4 EAS

AF:

0.162

Gnomad4 SAS

AF:

0.320

Gnomad4 FIN

AF:

0.308

Gnomad4 NFE

AF:

0.347

Gnomad4 OTH

AF:

0.362

Alfa

AF:

0.383

Hom.:

1451

Bravo

AF:

0.413

Asia WGS

AF:

0.242

AC:

840

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 44% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.30

DANN

Benign

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over