22-18167155-A-G

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.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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.494

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 (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/exons	MANE	UniProt
USP18	NM_017414.4	c.401-100A>G		intron_variant		ENST00000215794.8
USP18	XM_006724074.4	c.179-100A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP18	ENST00000215794.8	c.401-100A>G		intron_variant		1	NM_017414.4	P1
USP18	ENST00000699060.1	c.401-100A>G		intron_variant
USP18	ENST00000699061.1	n.147-100A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61371 AN: 151868 Hom.: 13465 Cov.: 30

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

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.: 30 AF XY: 0.399 AC XY: 29644 AN XY: 74298

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

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

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

Other links and lift over

dbSNP: rs9605536; hg19: chr22-18649922; COSMIC: COSV53172780;