chr1-1014451-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005101.4(ISG15):c.471C>T(p.Gly157Gly) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.92

Publications

7 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 -21 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 VariationId is 475281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

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.471C>T	p.Gly157Gly	synonymous	Exon 2 of 2	NP_005092.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ISG15	ENST00000649529.1	MANE Select	c.471C>T	p.Gly157Gly	synonymous	Exon 2 of 2	ENSP00000496832.1
ISG15	ENST00000624697.4	TSL:3	c.447C>T	p.Gly149Gly	synonymous	Exon 3 of 3	ENSP00000485643.1
ISG15	ENST00000624652.1	TSL:3	c.*16C>T		downstream_gene	N/A	ENSP00000485313.1

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1713

AN:

152160

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00713

AC:

1754

AN:

246070

AF XY:

0.00664

show subpopulations

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 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.:

Cov.:

AF XY:

0.00338

AC XY:

2441

AN XY:

722780

show subpopulations

African (AFR)

AF:

0.0298

AC:

994

AN:

33374

American (AMR)

AF:

0.00287

AC:

128

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.00549

AC:

143

AN:

26032

East Asian (EAS)

AF:

0.0250

AC:

987

AN:

39526

South Asian (SAS)

AF:

0.00475

AC:

409

AN:

86130

European-Finnish (FIN)

AF:

0.0183

AC:

953

AN:

52030

Middle Eastern (MID)

AF:

0.00904

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000804

AC:

891

AN:

1107572

Other (OTH)

AF:

0.00599

AC:

360

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

294

587

881

1174

1468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.0113

AC:

1715

AN:

152278

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

870

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0281

AC:

1168

AN:

41550

American (AMR)

AF:

0.00379

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.0278

AC:

144

AN:

5178

South Asian (SAS)

AF:

0.00601

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0191

AC:

203

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

68008

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

174

262

349

436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00498

Hom.:

Bravo

AF:

0.0107

EpiCase

AF:

0.00104

EpiControl

AF:

0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.66

CADD

Benign

1.1

(source)

DANN

Benign

0.79

PhyloP100

-4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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