chr1-1014011-G-C

Variant names:

• chr1-1014011-G-C
• NM_005101.4:c.31G>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.31G>C​(p.Ala11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A11T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ISG15 NM_005101.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250

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=0.14739528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISG15	NM_005101.4	c.31G>C	p.Ala11Pro	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.31G>C	p.Ala11Pro	missense_variant	Exon 2 of 2		NM_005101.4	ENSP00000496832.1
ISG15	ENST00000624697.4	c.7G>C	p.Ala3Pro	missense_variant	Exon 3 of 3	3		ENSP00000485643.1
ISG15	ENST00000624652.1	c.7G>C	p.Ala3Pro	missense_variant	Exon 3 of 3	3		ENSP00000485313.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450730 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719276

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: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T;T;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.39	T;T;.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.55	.;.;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	.;.;N;.
REVEL	Benign	0.085
Sift	Benign	0.047	.;.;D;.
Sift4G	Benign	0.084	T;T;T;.
Polyphen		0.0070	.;.;B;B
Vest4		0.10
MutPred		0.46		.;.;Loss of catalytic residue at A11 (P = 0.0189);Loss of catalytic residue at A11 (P = 0.0189);
MVP		0.32
MPC		0.34
ClinPred		0.11	T
GERP RS		0.66
Varity_R		0.58
gMVP		0.58

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-949391;