1-1014359-G-C

Variant names:

• chr1-1014359-G-C
• NM_005101.4:c.379G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005101.4(ISG15):​c.379G>C​(p.Glu127Gln) 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 1,461,146 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E127K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ISG15 NM_005101.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.562

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=0.20755756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISG15	NM_005101.4	c.379G>C	p.Glu127Gln	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.379G>C	p.Glu127Gln	missense_variant	Exon 2 of 2		NM_005101.4	ENSP00000496832.1
ISG15	ENST00000624697.4	c.355G>C	p.Glu119Gln	missense_variant	Exon 3 of 3	3		ENSP00000485643.1
ISG15	ENST00000624652.1	c.355G>C	p.Glu119Gln	missense_variant	Exon 3 of 3	3		ENSP00000485313.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461146 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.9
DANN	Benign	0.88
DEOGEN2	Benign	0.013	T;T;T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.65	T;T;.;T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.6	.;.;L;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.96	.;.;N;.
REVEL	Benign	0.17
Sift	Benign	0.36	.;.;T;.
Sift4G	Benign	0.34	T;D;T;.
Polyphen		0.67	.;.;P;P
Vest4		0.037
MutPred		0.47		.;.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.16
MPC		0.22
ClinPred		0.40	T
GERP RS		-1.6
Varity_R		0.38
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-949739;