chr22-18157736-G-A

Position:

• chr22-18157736-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017414.4(USP18):​c.73G>A​(p.Asp25Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,614,152 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (133 hom.)
• Consequence: USP18 NM_017414.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.425

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 (MetaRNN=0.002385646).
• BP6: Variant 22-18157736-G-A is Benign according to our data. Variant chr22-18157736-G-A is described in ClinVar as [Benign]. Clinvar id is 790895.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00148 (226/152264) while in subpopulation SAS AF= 0.0443 (214/4826). AF 95% confidence interval is 0.0395. There are 9 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP18	NM_017414.4	c.73G>A	p.Asp25Asn	missense_variant	2/11	ENST00000215794.8	NP_059110.2
USP18	XM_006724074.4			upstream_gene_variant			XP_006724137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP18	ENST00000215794.8	c.73G>A	p.Asp25Asn	missense_variant	2/11	1	NM_017414.4	ENSP00000215794	P1
USP18	ENST00000699060.1	c.73G>A	p.Asp25Asn	missense_variant	2/10			ENSP00000514107

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152146 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00574 AC: 1443 AN: 251446 Hom.: 58 AF XY: 0.00806 AC XY: 1095 AN XY: 135890

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0463

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00270 AC: 3953 AN: 1461888 Hom.: 133 Cov.: 31 AF XY: 0.00401 AC XY: 2913 AN XY: 727244

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0435

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152264 Hom.: 9 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74458

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0443

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00657 AC: 798

Asia WGS AF: 0.0150 AC: 51 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.017
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.020	D
Polyphen		0.24	B
Vest4		0.15
MVP		0.20
MPC		0.55
ClinPred		0.0080	T
GERP RS		0.43
Varity_R		0.075
gMVP		0.13

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: rs149306114; hg19: chr22-18640503;