NM_005101.4:c.31G>A

Variant names:

• chr1-1014011-G-A
• rs1241025790
• NM_005101.4:c.31G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005101.4(ISG15):​c.31G>A​(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,450,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 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. A11V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ISG15 NM_005101.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0250
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.31G>A	p.Ala11Thr	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.31G>A	p.Ala11Thr	missense	Exon 2 of 2	ENSP00000496832.1	P05161
	ISG15	ENST00000944242.1		c.31G>A	p.Ala11Thr	missense	Exon 5 of 5	ENSP00000614301.1
	ISG15	ENST00000624697.4	TSL:3	c.7G>A	p.Ala3Thr	missense	Exon 3 of 3	ENSP00000485643.1	A0A096LPJ4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248322 AF XY: 0.00000744

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1450730 Hom.: 0 Cov.: 31 AF XY: 0.00000556 AC XY: 4 AN XY: 719276

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39372

South Asian (SAS) AF: 0.0000815 AC: 7 AN: 85914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103620

Other (OTH) AF: 0.00 AC: 0 AN: 59838

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions

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	0.098
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.025
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MutPred		0.35		Loss of sheet (P = 0.1158)
MVP		0.16
MPC		0.20
ClinPred		0.12	T
GERP RS		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.21
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: 18

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

Other links and lift over

dbSNP: rs1241025790; hg19: chr1-949391;