rs750829395

Variant names:

• chr1-1013998-G-A
• rs750829395
• NM_005101.4:c.18G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1013998-G-A
• chr1-1013998-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_005101.4(ISG15):​c.18G>A​(p.Thr6Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,599,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ISG15 NM_005101.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.429
• 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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-1013998-G-A is Benign according to our data. Variant chr1-1013998-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1118824.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.429 with no splicing effect.

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.18G>A	p.Thr6Thr	synonymous	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.18G>A	p.Thr6Thr	synonymous	Exon 2 of 2	ENSP00000496832.1	P05161
	ISG15	ENST00000944242.1		c.18G>A	p.Thr6Thr	synonymous	Exon 5 of 5	ENSP00000614301.1
	ISG15	ENST00000624697.4	TSL:3	c.-7G>A		5_prime_UTR	Exon 3 of 3	ENSP00000485643.1	A0A096LPJ4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000243 AC: 6 AN: 246456 AF XY: 0.0000300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000152 AC: 22 AN: 1447548 Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 11 AN XY: 717212

African (AFR) AF: 0.00 AC: 0 AN: 33256

American (AMR) AF: 0.0000225 AC: 1 AN: 44362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39332

South Asian (SAS) AF: 0.00 AC: 0 AN: 85534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1101486

Other (OTH) AF: 0.0000167 AC: 1 AN: 59728

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs750829395; hg19: chr1-949378;