1-1014228-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:5O:1

Conservation

PhyloP100: -0.396

Publications

51 publications found

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 Gene-Disease associations (from GenCC):

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ISG15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005101.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISG15	NM_005101.4	MANE Select	c.248G>A	p.Ser83Asn	missense	Exon 2 of 2	NP_005092.1	P05161

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ISG15	ENST00000649529.1	MANE Select	c.248G>A	p.Ser83Asn	missense	Exon 2 of 2	ENSP00000496832.1	P05161
ISG15	ENST00000944242.1		c.248G>A	p.Ser83Asn	missense	Exon 5 of 5	ENSP00000614301.1
ISG15	ENST00000624697.4	TSL:3	c.224G>A	p.Ser75Asn	missense	Exon 3 of 3	ENSP00000485643.1	A0A096LPJ4

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

GnomAD2 exomes

AF:

0.359

AC:

89869

AN:

250098

AF XY:

0.362

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 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

African (AFR)

AF:

0.407

AC:

13626

AN:

33476

American (AMR)

AF:

0.250

AC:

11195

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

8091

AN:

26130

East Asian (EAS)

AF:

0.184

AC:

7315

AN:

39696

South Asian (SAS)

AF:

0.342

AC:

29540

AN:

86258

European-Finnish (FIN)

AF:

0.467

AC:

24653

AN:

52844

Middle Eastern (MID)

AF:

0.300

AC:

1731

AN:

5768

European-Non Finnish (NFE)

AF:

0.396

AC:

440786

AN:

1111920

Other (OTH)

AF:

0.368

AC:

22224

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

22663

45326

67989

90652

113315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13528

27056

40584

54112

67640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.384

AC:

58393

AN:

152218

Hom.:

11555

Cov.:

AF XY:

0.383

AC XY:

28525

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.405

AC:

16842

AN:

41538

American (AMR)

AF:

0.281

AC:

4299

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

1074

AN:

3470

East Asian (EAS)

AF:

0.203

AC:

1052

AN:

5184

South Asian (SAS)

AF:

0.349

AC:

1686

AN:

4828

European-Finnish (FIN)

AF:

0.481

AC:

5101

AN:

10594

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.399

AC:

27120

AN:

67980

Other (OTH)

AF:

0.364

AC:

769

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1934

3868

5801

7735

9669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.380

Hom.:

24187

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (2)

not specified (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.2

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.016

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0011

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

PhyloP100

-0.40

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.0

REVEL

Benign

0.047

Sift

Benign

0.31

Sift4G

Benign

0.11

Polyphen

0.010

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over