1-1013541-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005101.4(ISG15):c.-33T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 1,612,360 control chromosomes in the GnomAD database, including 730,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 62181 hom., cov: 33)

Exomes 𝑓: 0.96 ( 668050 hom. )

Consequence

ISG15
NM_005101.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.966

Publications

18 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, Labcorp Genetics (formerly Invitae), Orphanet

ISG15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 1-1013541-T-C is Benign according to our data. Variant chr1-1013541-T-C is described in ClinVar as Benign. ClinVar VariationId is 1185394.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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISG15	NM_005101.4	MANE Select	c.-33T>C		5_prime_UTR	Exon 1 of 2	NP_005092.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ISG15	ENST00000649529.1	MANE Select	c.-33T>C	5_prime_UTR	Exon 1 of 2	ENSP00000496832.1
ISG15	ENST00000624697.4	TSL:3	c.-21-443T>C	intron	N/A	ENSP00000485643.1
ISG15	ENST00000624652.1	TSL:3	c.-21-443T>C	intron	N/A	ENSP00000485313.1

Frequencies

GnomAD3 genomes

AF:

0.899

AC:

136681

AN:

152066

Hom.:

62165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.743

Gnomad AMI

AF:

0.980

Gnomad AMR

AF:

0.936

Gnomad ASJ

AF:

0.910

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.968

Gnomad FIN

AF:

0.975

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.959

Gnomad OTH

AF:

0.907

GnomAD2 exomes

AF:

0.946

AC:

236864

AN:

250474

AF XY:

0.949

show subpopulations

Gnomad AFR exome

AF:

0.738

Gnomad AMR exome

AF:

0.958

Gnomad ASJ exome

AF:

0.904

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.971

Gnomad NFE exome

AF:

0.958

Gnomad OTH exome

AF:

0.938

GnomAD4 exome

AF:

0.956

AC:

1395472

AN:

1460178

Hom.:

668050

Cov.:

AF XY:

0.956

AC XY:

694436

AN XY:

726480

show subpopulations

African (AFR)

AF:

0.728

AC:

24342

AN:

33416

American (AMR)

AF:

0.954

AC:

42645

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.904

AC:

23619

AN:

26120

East Asian (EAS)

AF:

1.00

AC:

39696

AN:

39700

South Asian (SAS)

AF:

0.961

AC:

82891

AN:

86226

European-Finnish (FIN)

AF:

0.970

AC:

51298

AN:

52868

Middle Eastern (MID)

AF:

0.861

AC:

4955

AN:

5752

European-Non Finnish (NFE)

AF:

0.962

AC:

1069345

AN:

1111046

Other (OTH)

AF:

0.939

AC:

56681

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

2838

5677

8515

11354

14192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21596

43192

64788

86384

107980

<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:

0.899

AC:

136739

AN:

152182

Hom.:

62181

Cov.:

AF XY:

0.900

AC XY:

66993

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.742

AC:

30798

AN:

41480

American (AMR)

AF:

0.936

AC:

14311

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.910

AC:

3158

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5173

AN:

5174

South Asian (SAS)

AF:

0.968

AC:

4665

AN:

4820

European-Finnish (FIN)

AF:

0.975

AC:

10344

AN:

10604

Middle Eastern (MID)

AF:

0.884

AC:

260

AN:

294

European-Non Finnish (NFE)

AF:

0.959

AC:

65221

AN:

68026

Other (OTH)

AF:

0.908

AC:

1917

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

655

1310

1965

2620

3275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.926

Hom.:

58411

Bravo

AF:

0.889

Asia WGS

AF:

0.966

AC:

3361

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 02, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 96. Only high quality variants are reported.

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

3.2

(source)

DANN

Benign

0.58

PhyloP100

-0.97

PromoterAI

0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=294/6

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over