1-1014228-G-A

Position:

chr1-1014228-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_005101.4(ISG15):c.248G>A(p.Ser83Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,414 control chromosomes in the GnomAD database, including 120,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11555 hom., cov: 35)

Exomes 𝑓: 0.38 ( 108952 hom. )

Consequence

ISG15
NM_005101.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -0.396

Variant links:

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]

ISG15 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a mutagenesis_site Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases. (size 0) in uniprot entity ISG15_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0010858476).

BP6

Variant 1-1014228-G-A is Benign according to our data. Variant chr1-1014228-G-A is described in ClinVar as [Benign]. Clinvar id is 402986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISG15	NM_005101.4 linkuse as main transcript	c.248G>A	p.Ser83Asn	missense_variant	2/2	ENST00000649529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ISG15	ENST00000649529.1 linkuse as main transcript	c.248G>A	p.Ser83Asn	missense_variant	2/2		NM_005101.4	P1
ISG15	ENST00000624697.4 linkuse as main transcript	c.224G>A	p.Ser75Asn	missense_variant	3/3	3
ISG15	ENST00000624652.1 linkuse as main transcript	c.224G>A	p.Ser75Asn	missense_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.384

AC:

58370

AN:

152098

Hom.:

11551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.406

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.203

Gnomad SAS

AF:

0.349

Gnomad FIN

AF:

0.481

Gnomad MID

AF:

0.328

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.368

GnomAD3 exomes

AF:

0.359

AC:

89869

AN:

250098

Hom.:

17226

AF XY:

0.362

AC XY:

49094

AN XY:

135512

show subpopulations

Gnomad AFR exome

AF:

0.415

Gnomad AMR exome

AF:

0.245

Gnomad ASJ exome

AF:

0.314

Gnomad EAS exome

AF:

0.200

Gnomad SAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.467

Gnomad NFE exome

AF:

0.400

Gnomad OTH exome

AF:

0.368

GnomAD4 exome

AF:

0.383

AC:

559161

AN:

1461196

Hom.:

108952

Cov.:

AF XY:

0.382

AC XY:

277736

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.407

Gnomad4 AMR exome

AF:

0.250

Gnomad4 ASJ exome

AF:

0.310

Gnomad4 EAS exome

AF:

0.184

Gnomad4 SAS exome

AF:

0.342

Gnomad4 FIN exome

AF:

0.467

Gnomad4 NFE exome

AF:

0.396

Gnomad4 OTH exome

AF:

0.368

GnomAD4 genome

AF:

0.384

AC:

58393

AN:

152218

Hom.:

11555

Cov.:

AF XY:

0.383

AC XY:

28525

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.405

Gnomad4 AMR

AF:

0.281

Gnomad4 ASJ

AF:

0.310

Gnomad4 EAS

AF:

0.203

Gnomad4 SAS

AF:

0.349

Gnomad4 FIN

AF:

0.481

Gnomad4 NFE

AF:

0.399

Gnomad4 OTH

AF:

0.364

Alfa

AF:

0.379

Hom.:

14807

Bravo

AF:

0.368

TwinsUK

AF:

0.389

AC:

1442

ALSPAC

AF:

0.394

AC:

1517

ESP6500AA

AF:

0.415

AC:

1827

ESP6500EA

AF:

0.395

AC:

3396

ExAC

AF:

0.369

AC:

44779

Asia WGS

AF:

0.277

AC:

965

AN:

3478

EpiCase

AF:

0.385

EpiControl

AF:

0.387

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 49% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.2

DANN

Benign

0.84

DEOGEN2

Benign

0.016

T;T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.48

T;T;.;T

MetaRNN

Benign

0.0011

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

.;.;L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.0

.;.;N;.

REVEL

Benign

0.047

Sift

Benign

0.31

.;.;T;.

Sift4G

Benign

0.11

T;T;T;.

Polyphen

0.010

.;.;B;B

Vest4

0.022

MPC

0.19

ClinPred

0.0036

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over