NM_005101.4:c.491G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_005101.4(ISG15):c.491G>C(p.Arg164Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,600,986 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 34)

Exomes 𝑓: 0.000074 ( 1 hom. )

Consequence

ISG15
NM_005101.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.67

Publications

2 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004445493).

BP6

Variant 1-1014471-G-C is Benign according to our data. Variant chr1-1014471-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 475282.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISG15	NM_005101.4 link	c.491G>C	p.Arg164Pro	missense_variant	Exon 2 of 2	ENST00000649529.1	NP_005092.1	P05161

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ISG15	ENST00000649529.1 link	c.491G>C	p.Arg164Pro	missense_variant	Exon 2 of 2		NM_005101.4	ENSP00000496832.1	P05161
ISG15	ENST00000624697.4 link	c.467G>C	p.Arg156Pro	missense_variant	Exon 3 of 3	3		ENSP00000485643.1	A0A096LPJ4
ISG15	ENST00000624652.1 link	c.*36G>C		downstream_gene_variant		3		ENSP00000485313.1	A0A096LNZ9

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000203

AC:

AN:

241544

AF XY:

0.000136

show subpopulations

Gnomad AFR exome

AF:

0.00251

Gnomad AMR exome

AF:

0.000176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000277

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000739

AC:

107

AN:

1448650

Hom.:

Cov.:

AF XY:

0.0000640

AC XY:

AN XY:

718588

show subpopulations

African (AFR)

AF:

0.00232

AC:

AN:

33214

American (AMR)

AF:

0.000181

AC:

AN:

44132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25730

East Asian (EAS)

AF:

0.00

AC:

AN:

39416

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51300

Middle Eastern (MID)

AF:

0.000698

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00000816

AC:

AN:

1103596

Other (OTH)

AF:

0.000134

AC:

AN:

59818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000716

AC:

109

AN:

152336

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41584

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000136

Hom.:

Bravo

AF:

0.000778

ESP6500AA

AF:

0.00206

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000198

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.0050

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.0095

T;T;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.45

T;.;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;N

PhyloP100

-2.7

PrimateAI

Benign

0.31

PROVEAN

Benign

0.21

.;N;.

REVEL

Benign

0.012

Sift

Benign

0.037

.;D;.

Sift4G

Uncertain

0.020

D;D;.

Polyphen

0.0

.;B;B

Vest4

0.11

MVP

0.040

MPC

0.30

ClinPred

0.0047

GERP RS

-5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.12

gMVP

0.51

Mutation Taster

=99/1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over