rs1921

Variant names:

• chr1-1014228-G-A
• rs1921
• NM_005101.4:c.248G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1014228-G-A
• chr1-1014228-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_005101.4(ISG15):​c.248G>A​(p.Ser83Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,414 control chromosomes in the GnomAD database, including 120,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11555 hom., cov: 35)
  • Exomes 𝑓: 0.38 (108952 hom.)
• Consequence: ISG15 NM_005101.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.396

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]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a mutagenesis_site Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases. (size 0) in uniprot entity ISG15_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0010858476).
• BP6: Variant 1-1014228-G-A is Benign according to our data. Variant chr1-1014228-G-A is described in ClinVar as [Benign]. Clinvar id is 402986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISG15	NM_005101.4	c.248G>A	p.Ser83Asn	missense_variant	Exon 2 of 2	ENST00000649529.1	NP_005092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISG15	ENST00000649529.1	c.248G>A	p.Ser83Asn	missense_variant	Exon 2 of 2		NM_005101.4	ENSP00000496832.1
ISG15	ENST00000624697.4	c.224G>A	p.Ser75Asn	missense_variant	Exon 3 of 3	3		ENSP00000485643.1
ISG15	ENST00000624652.1	c.224G>A	p.Ser75Asn	missense_variant	Exon 3 of 3	3		ENSP00000485313.1

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58370 AN: 152098 Hom.: 11551 Cov.: 35

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.368

GnomAD2 exomes AF: 0.359 AC: 89869 AN: 250098 AF XY: 0.362

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.467

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.383 AC: 559161 AN: 1461196 Hom.: 108952 Cov.: 74 AF XY: 0.382 AC XY: 277736 AN XY: 726914

Gnomad4 AFR exome AF: 0.407 AC: 13626 AN: 33476

Gnomad4 AMR exome AF: 0.250 AC: 11195 AN: 44724

Gnomad4 ASJ exome AF: 0.310 AC: 8091 AN: 26130

Gnomad4 EAS exome AF: 0.184 AC: 7315 AN: 39696

Gnomad4 SAS exome AF: 0.342 AC: 29540 AN: 86258

Gnomad4 FIN exome AF: 0.467 AC: 24653 AN: 52844

Gnomad4 NFE exome AF: 0.396 AC: 440786 AN: 1111920

Gnomad4 Remaining exome AF: 0.368 AC: 22224 AN: 60380

GnomAD4 genome AF: 0.384 AC: 58393 AN: 152218 Hom.: 11555 Cov.: 35 AF XY: 0.383 AC XY: 28525 AN XY: 74422

Gnomad4 AFR AF: 0.405 AC: 0.40546 AN: 0.40546

Gnomad4 AMR AF: 0.281 AC: 0.280907 AN: 0.280907

Gnomad4 ASJ AF: 0.310 AC: 0.30951 AN: 0.30951

Gnomad4 EAS AF: 0.203 AC: 0.202932 AN: 0.202932

Gnomad4 SAS AF: 0.349 AC: 0.349213 AN: 0.349213

Gnomad4 FIN AF: 0.481 AC: 0.481499 AN: 0.481499

Gnomad4 NFE AF: 0.399 AC: 0.398941 AN: 0.398941

Gnomad4 OTH AF: 0.364 AC: 0.363765 AN: 0.363765

Alfa AF: 0.380 Hom.: 24187

Bravo AF: 0.368

TwinsUK AF: 0.389 AC: 1442

ALSPAC AF: 0.394 AC: 1517

ESP6500AA AF: 0.415 AC: 1827

ESP6500EA AF: 0.395 AC: 3396

ExAC AF: 0.369 AC: 44779

Asia WGS AF: 0.277 AC: 965 AN: 3478

EpiCase AF: 0.385

EpiControl AF: 0.387

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 12, 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 49% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.2
DANN	Benign	0.84
DEOGEN2	Benign	0.016	T;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.48	T;T;.;T
MetaRNN	Benign	0.0011	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	.;.;L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.0	.;.;N;.
REVEL	Benign	0.047
Sift	Benign	0.31	.;.;T;.
Sift4G	Benign	0.11	T;T;T;.
Polyphen		0.010	.;.;B;B
Vest4		0.022
MPC		0.19
ClinPred		0.0036	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.28
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1921; hg19: chr1-949608; COSMIC: COSV65106391; COSMIC: COSV65106391;