NM_005101.4:c.17C>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005101.4(ISG15):​c.17C>A​(p.Thr6Lys) 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. 16/22 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. T6M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 35)
• Consequence: ISG15 NM_005101.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030810863).

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>A	p.Thr6Lys	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>A	p.Thr6Lys	missense	Exon 2 of 2	ENSP00000496832.1	P05161
	ISG15	ENST00000944242.1		c.17C>A	p.Thr6Lys	missense	Exon 5 of 5	ENSP00000614301.1
	ISG15	ENST00000624697.4	TSL:3	c.-8C>A		5_prime_UTR	Exon 3 of 3	ENSP00000485643.1	A0A096LPJ4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.047
DANN	Benign	0.89
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.17	N
PhyloP100		-1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.058
Sift	Benign	0.69	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.47		Gain of MoRF binding (P = 0.013)
MVP		0.030
MPC		0.25
ClinPred		0.13	T
GERP RS		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.090
gMVP		0.41
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;