rs368865539

Positions:

chr1-1014255-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005101.4(ISG15):c.275G>A(p.Arg92His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 36)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ISG15
NM_005101.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.0380

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13380209).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISG15	NM_005101.4 linkuse as main transcript	c.275G>A	p.Arg92His	missense_variant	2/2	ENST00000649529.1	NP_005092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ISG15	ENST00000649529.1 linkuse as main transcript	c.275G>A	p.Arg92His	missense_variant	2/2		NM_005101.4	ENSP00000496832	P1
ISG15	ENST00000624697.4 linkuse as main transcript	c.251G>A	p.Arg84His	missense_variant	3/3	3		ENSP00000485643
ISG15	ENST00000624652.1 linkuse as main transcript	c.251G>A	p.Arg84His	missense_variant	3/3	3		ENSP00000485313

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

250312

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135614

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461242

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726928

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 92 of the ISG15 protein (p.Arg92His). This variant is present in population databases (rs368865539, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ISG15-related conditions. ClinVar contains an entry for this variant (Variation ID: 571208). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

T;T;T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.73

T;T;.;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.5

.;.;M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.8

.;.;D;.

REVEL

Benign

0.17

Sift

Benign

0.078

.;.;T;.

Sift4G

Uncertain

0.036

D;T;D;.

Polyphen

0.72

.;.;P;P

Vest4

0.077

MVP

0.61

MPC

0.27

ClinPred

0.18

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.37

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