rs116002608

chr1-1014451-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_005101.4(ISG15):c.471C>T(p.Gly157=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,607,432 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 34)
  • Exomes 𝑓: 0.0034 (35 hom.)
• Consequence: ISG15 NM_005101.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.92

Genes affected

ISG15 (HGNC:4053): (ISG15 ubiquitin like modifier) The protein encoded by this gene is a ubiquitin-like protein that is conjugated to intracellular target proteins upon activation by interferon-alpha and interferon-beta. Several functions have been ascribed to the encoded protein, including chemotactic activity towards neutrophils, direction of ligated target proteins to intermediate filaments, cell-to-cell signaling, and antiviral activity during viral infections. While conjugates of this protein have been found to be noncovalently attached to intermediate filaments, this protein is sometimes secreted. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-1014451-C-T is Benign according to our data. Variant chr1-1014451-C-T is described in ClinVar as [Benign]. Clinvar id is 475281.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1715/152278) while in subpopulation AFR AF= 0.0281 (1168/41550). AF 95% confidence interval is 0.0268. There are 21 homozygotes in gnomad4. There are 870 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISG15	NM_005101.4	c.471C>T	p.Gly157=	synonymous_variant	2/2	ENST00000649529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISG15	ENST00000649529.1	c.471C>T	p.Gly157=	synonymous_variant	2/2		NM_005101.4	P1
ISG15	ENST00000624697.4	c.447C>T	p.Gly149=	synonymous_variant	3/3	3
ISG15	ENST00000624652.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1713 AN: 152160 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00713 AC: 1754 AN: 246070 Hom.: 14 AF XY: 0.00664 AC XY: 891 AN XY: 134110

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.00569

Gnomad EAS exome AF: 0.0219

Gnomad SAS exome AF: 0.00466

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.00712

GnomAD4 exome AF: 0.00338 AC: 4917 AN: 1455154 Hom.: 35 Cov.: 37 AF XY: 0.00338 AC XY: 2441 AN XY: 722780

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.00549

Gnomad4 EAS exome AF: 0.0250

Gnomad4 SAS exome AF: 0.00475

Gnomad4 FIN exome AF: 0.0183

Gnomad4 NFE exome AF: 0.000804

Gnomad4 OTH exome AF: 0.00599

GnomAD4 genome AF: 0.0113 AC: 1715 AN: 152278 Hom.: 21 Cov.: 34 AF XY: 0.0117 AC XY: 870 AN XY: 74454

Gnomad4 AFR AF: 0.0281

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.0278

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00498 Hom.: 5

Bravo AF: 0.0107

EpiCase AF: 0.00104

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	1.1
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs116002608; hg19: chr1-949831; COSMIC: COSV65106772; COSMIC: COSV65106772;