rs61766284

chr1-1014217-C-Gchr1-1014217-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005101.4(ISG15):c.237C>G(p.Asp79Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D79D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ISG15 NM_005101.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.32

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042057842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISG15	NM_005101.4	c.237C>G	p.Asp79Glu	missense_variant	2/2	ENST00000649529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISG15	ENST00000649529.1	c.237C>G	p.Asp79Glu	missense_variant	2/2		NM_005101.4	P1
ISG15	ENST00000624697.4	c.213C>G	p.Asp71Glu	missense_variant	3/3	3
ISG15	ENST00000624652.1	c.213C>G	p.Asp71Glu	missense_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250062 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461184 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.0050
Dann	Benign	0.44
DEOGEN2	Benign	0.0096	T;T;T;T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.44	T;T;.;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.042	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
Sift4G	Benign	0.54	T;T;T;.
Polyphen		0.052	.;.;B;B
Vest4		0.049
MutPred		0.44		.;.;Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.014
MPC		0.19
ClinPred		0.043	T
GERP RS		-8.0
Varity_R		0.23
gMVP		0.14

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: rs61766284; hg19: chr1-949597;