rs368865539

chr1-1014255-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0380

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

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	UniProt
ISG15	NM_005101.4	c.275G>A	p.Arg92His	missense_variant	2/2	ENST00000649529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISG15	ENST00000649529.1	c.275G>A	p.Arg92His	missense_variant	2/2		NM_005101.4	P1
ISG15	ENST00000624697.4	c.251G>A	p.Arg84His	missense_variant	3/3	3
ISG15	ENST00000624652.1	c.251G>A	p.Arg84His	missense_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152242 Hom.: 0 Cov.: 36

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: 9 AN: 250312 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135614

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: 27 AN: 1461242 Hom.: 0 Cov.: 67 AF XY: 0.0000165 AC XY: 12 AN XY: 726928

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: 10 AN: 152360 Hom.: 0 Cov.: 36 AF XY: 0.0000268 AC XY: 2 AN XY: 74500

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.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	15
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	N
LIST_S2	Benign	0.73	T;T;.;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	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	T
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

Other links and lift over

dbSNP: rs368865539; hg19: chr1-949635;