rs5992185

Variant names:

• chr22-18151211-A-C
• rs5992185
• NM_017414.4:c.-107+989A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017414.4(USP18):​c.-107+989A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 151,846 control chromosomes in the GnomAD database, including 13,125 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13125 hom., cov: 32)
• Consequence: USP18 NM_017414.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• Publications: 4 publications found

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, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP18	NM_017414.4	MANE Select	c.-107+989A>C		intron	N/A	NP_059110.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP18	ENST00000215794.8	TSL:1 MANE Select	c.-107+989A>C		intron	N/A	ENSP00000215794.7
	USP18	ENST00000699060.2		c.-107+989A>C		intron	N/A	ENSP00000514107.1
	USP18	ENST00000715585.1		n.-107+989A>C		intron	N/A	ENSP00000520484.1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60347 AN: 151728 Hom.: 13105 Cov.: 32

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.0545

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.369

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.398 AC: 60418 AN: 151846 Hom.: 13125 Cov.: 32 AF XY: 0.393 AC XY: 29140 AN XY: 74216

African (AFR) AF: 0.566 AC: 23411 AN: 41366

American (AMR) AF: 0.324 AC: 4944 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1302 AN: 3466

East Asian (EAS) AF: 0.0544 AC: 281 AN: 5164

South Asian (SAS) AF: 0.233 AC: 1121 AN: 4812

European-Finnish (FIN) AF: 0.348 AC: 3677 AN: 10552

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24305 AN: 67926

Other (OTH) AF: 0.365 AC: 765 AN: 2094

Alfa AF: 0.367 Hom.: 34982

Bravo AF: 0.402

Asia WGS AF: 0.163 AC: 571 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.9
DANN	Benign	0.42
PhyloP100		0.035
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5992185; hg19: chr22-18633978;