1-1013997-C-T

Variant names:

• chr1-1013997-C-T
• rs199853706
• NM_005101.4:c.17C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005101.4(ISG15):​c.17C>T​(p.Thr6Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000319 in 1,599,210 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T6K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: ISG15 NM_005101.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.31
• Publications: 0 publications found

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]

ISG15 Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06755617).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005101.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISG15	NM_005101.4	MANE Select	c.17C>T	p.Thr6Met	missense	Exon 2 of 2	NP_005092.1	P05161

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISG15	ENST00000649529.1	MANE Select	c.17C>T	p.Thr6Met	missense	Exon 2 of 2	ENSP00000496832.1	P05161
	ISG15	ENST00000624697.4	TSL:3	c.-8C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000485643.1	A0A096LPJ4
	ISG15	ENST00000624652.1	TSL:3	c.-8C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000485313.1	A0A096LNZ9

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152240 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000106 AC: 26 AN: 245710 AF XY: 0.0000677

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000612

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000304 AC: 44 AN: 1446852 Hom.: 0 Cov.: 31 AF XY: 0.0000279 AC XY: 20 AN XY: 716818

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.000542 AC: 24 AN: 44314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52356

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1101220

Other (OTH) AF: 0.0000670 AC: 4 AN: 59700

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152358 Hom.: 0 Cov.: 35 AF XY: 0.0000268 AC XY: 2 AN XY: 74508

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.000326 AC: 5 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000286 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.3
DANN	Benign	0.94
DEOGEN2	Benign	0.34	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		-1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.16
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.058	T
Polyphen		0.93	P
Vest4		0.14
MVP		0.040
MPC		0.51
ClinPred		0.15	T
GERP RS		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.35
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs199853706; hg19: chr1-949377;