1-1013490-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000624697.4(ISG15):c.-21-494C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.948 in 1,447,158 control chromosomes in the GnomAD database, including 652,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62121 hom., cov: 34)
  • Exomes 𝑓: 0.95 (590006 hom.)
• Consequence: ISG15 ENST00000624697.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.01

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 1-1013490-C-G is Benign according to our data. Variant chr1-1013490-C-G is described in ClinVar as [Benign]. Clinvar id is 1185393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISG15	NM_005101.4			upstream_gene_variant		ENST00000649529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISG15	ENST00000624652.1	c.-21-494C>G		intron_variant		3
ISG15	ENST00000624697.4	c.-21-494C>G		intron_variant		3
ISG15	ENST00000649529.1			upstream_gene_variant			NM_005101.4	P1

Frequencies

GnomAD3 genomes AF: 0.898 AC: 136585 AN: 152022 Hom.: 62105 Cov.: 34

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.981

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.968

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.959

Gnomad OTH AF: 0.907

GnomAD4 exome AF: 0.954 AC: 1234934 AN: 1295018 Hom.: 590006 Cov.: 19 AF XY: 0.954 AC XY: 623299 AN XY: 653320

Gnomad4 AFR exome AF: 0.721

Gnomad4 AMR exome AF: 0.954

Gnomad4 ASJ exome AF: 0.903

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.960

Gnomad4 FIN exome AF: 0.970

Gnomad4 NFE exome AF: 0.961

Gnomad4 OTH exome AF: 0.937

GnomAD4 genome AF: 0.898 AC: 136643 AN: 152140 Hom.: 62121 Cov.: 34 AF XY: 0.900 AC XY: 66951 AN XY: 74384

Gnomad4 AFR AF: 0.741

Gnomad4 AMR AF: 0.936

Gnomad4 ASJ AF: 0.910

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.968

Gnomad4 FIN AF: 0.976

Gnomad4 NFE AF: 0.959

Gnomad4 OTH AF: 0.908

Alfa AF: 0.926 Hom.: 3709

Bravo AF: 0.888

Asia WGS AF: 0.967 AC: 3364 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 14, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 87. Only high quality variants are reported. -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.53
Dann	Benign	0.47

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: rs4615788; hg19: chr1-948870;