1-1014228-G-C

Position:

• chr1-1014228-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005101.4(ISG15):​c.248G>C​(p.Ser83Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S83N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: ISG15 NM_005101.4 missense
• Clinical Significance: Not reported in ClinVar
• 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

Verdict is Uncertain_significance. Variant got 2 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12672523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISG15	NM_005101.4	c.248G>C	p.Ser83Thr	missense_variant	2/2	ENST00000649529.1	NP_005092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ISG15	ENST00000649529.1	c.248G>C	p.Ser83Thr	missense_variant	2/2		NM_005101.4	ENSP00000496832.1
ISG15	ENST00000624697.4	c.224G>C	p.Ser75Thr	missense_variant	3/3	3		ENSP00000485643.1
ISG15	ENST00000624652.1	c.224G>C	p.Ser75Thr	missense_variant	3/3	3		ENSP00000485313.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 74

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.4
DANN	Benign	0.87
DEOGEN2	Benign	0.027	T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.58	T;T;.;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	.;.;M;M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	.;.;N;.
REVEL	Benign	0.098
Sift	Benign	0.12	.;.;T;.
Sift4G	Benign	0.14	T;D;T;.
Polyphen		0.59	.;.;P;P
Vest4		0.094
MutPred		0.34		.;.;Loss of disorder (P = 0.1167);Loss of disorder (P = 0.1167);
MVP		0.040
MPC		0.19
ClinPred		0.20	T
GERP RS		-2.4
Varity_R		0.44
gMVP		0.24

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;