22-18157533-G-A

Variant names:

• chr22-18157533-G-A
• rs2252257
• NM_017414.4:c.-106-25G>A

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.-106-25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,186,556 control chromosomes in the GnomAD database, including 33,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (6048 hom., cov: 32)
  • Exomes 𝑓: 0.20 (27619 hom.)
• Consequence: USP18 NM_017414.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.759

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=-0.96).
• BP6: Variant 22-18157533-G-A is Benign according to our data. Variant chr22-18157533-G-A is described in ClinVar as [Benign]. Clinvar id is 2628193.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP18	NM_017414.4	c.-106-25G>A		intron_variant	Intron 1 of 10	ENST00000215794.8	NP_059110.2
USP18	XM_006724074.4	c.-392G>A		upstream_gene_variant			XP_006724137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP18	ENST00000215794.8	c.-106-25G>A		intron_variant	Intron 1 of 10	1	NM_017414.4	ENSP00000215794.7
USP18	ENST00000699060.1	c.-106-25G>A		intron_variant	Intron 1 of 9			ENSP00000514107.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38332 AN: 151920 Hom.: 6012 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.201 AC: 208380 AN: 1034518 Hom.: 27619 Cov.: 13 AF XY: 0.203 AC XY: 106014 AN XY: 522504

Gnomad4 AFR exome AF: 0.348

Gnomad4 AMR exome AF: 0.468

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.596

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.253 AC: 38425 AN: 152038 Hom.: 6048 Cov.: 32 AF XY: 0.254 AC XY: 18905 AN XY: 74326

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.633

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.224

Alfa AF: 0.193 Hom.: 6809

Bravo AF: 0.274

Asia WGS AF: 0.463 AC: 1605 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

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 46% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.36
DANN	Benign	0.89

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: rs2252257; hg19: chr22-18640300; COSMIC: COSV53174982;