chr1-1014042-G-A

Position:

chr1-1014042-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005101.4(ISG15):c.62G>A(p.Ser21Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00087 in 1,612,130 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 6 hom., cov: 35)

Exomes 𝑓: 0.00048 ( 6 hom. )

Consequence

ISG15
NM_005101.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.676

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039076805).

BP6

Variant 1-1014042-G-A is Benign according to our data. Variant chr1-1014042-G-A is described in ClinVar as [Benign]. Clinvar id is 475283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000484 (707/1459768) while in subpopulation AFR AF= 0.0171 (573/33460). AF 95% confidence interval is 0.016. There are 6 homozygotes in gnomad4_exome. There are 309 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISG15	NM_005101.4 linkuse as main transcript	c.62G>A	p.Ser21Asn	missense_variant	2/2	ENST00000649529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ISG15	ENST00000649529.1 linkuse as main transcript	c.62G>A	p.Ser21Asn	missense_variant	2/2		NM_005101.4	P1
ISG15	ENST00000624697.4 linkuse as main transcript	c.38G>A	p.Ser13Asn	missense_variant	3/3	3
ISG15	ENST00000624652.1 linkuse as main transcript	c.38G>A	p.Ser13Asn	missense_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.00452

AC:

688

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

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:

0.000103

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00131

AC:

328

AN:

250348

Hom.:

AF XY:

0.000885

AC XY:

120

AN XY:

135524

show subpopulations

Gnomad AFR exome

AF:

0.0176

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000886

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000484

AC:

707

AN:

1459768

Hom.:

Cov.:

AF XY:

0.000426

AC XY:

309

AN XY:

725796

show subpopulations

Gnomad4 AFR exome

AF:

0.0171

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.00456

AC:

695

AN:

152362

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0156

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00538

ESP6500AA

AF:

0.0161

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00163

AC:

198

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.13

DANN

Benign

0.82

DEOGEN2

Benign

0.016

T;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.15

T;T;.;T

MetaRNN

Benign

0.0039

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.59

.;.;N;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

0.34

.;.;N;.

REVEL

Benign

0.096

Sift

Benign

0.73

.;.;T;.

Sift4G

Benign

0.89

T;T;T;.

Polyphen

0.0

.;.;B;B

Vest4

0.086

MVP

0.19

MPC

0.19

ClinPred

0.0011

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.21

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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