NM_005101.4:c.237C>T

Variant names:

• chr1-1014217-C-T
• rs61766284
• NM_005101.4:c.237C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005101.4(ISG15):​c.237C>T​(p.Asp79Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,613,534 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (22 hom., cov: 35)
  • Exomes 𝑓: 0.0073 (92 hom.)
• Consequence: ISG15 NM_005101.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.32
• Publications: 2 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-1014217-C-T is Benign according to our data. Variant chr1-1014217-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.32 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

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.237C>T	p.Asp79Asp	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.237C>T	p.Asp79Asp	synonymous	Exon 2 of 2	ENSP00000496832.1	P05161
	ISG15	ENST00000944242.1		c.237C>T	p.Asp79Asp	synonymous	Exon 5 of 5	ENSP00000614301.1
	ISG15	ENST00000624697.4	TSL:3	c.213C>T	p.Asp71Asp	synonymous	Exon 3 of 3	ENSP00000485643.1	A0A096LPJ4

Frequencies

GnomAD3 genomes AF: 0.00751 AC: 1144 AN: 152236 Hom.: 22 Cov.: 35

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00756

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00852 AC: 2130 AN: 250062 AF XY: 0.00830

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0477

Gnomad NFE exome AF: 0.00854

Gnomad OTH exome AF: 0.00817

GnomAD4 exome AF: 0.00725 AC: 10598 AN: 1461180 Hom.: 92 Cov.: 32 AF XY: 0.00701 AC XY: 5097 AN XY: 726894

African (AFR) AF: 0.00125 AC: 42 AN: 33476

American (AMR) AF: 0.00145 AC: 65 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.0461 AC: 2436 AN: 52800

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00695 AC: 7724 AN: 1111950

Other (OTH) AF: 0.00522 AC: 315 AN: 60380

GnomAD4 genome AF: 0.00751 AC: 1144 AN: 152354 Hom.: 22 Cov.: 35 AF XY: 0.00942 AC XY: 702 AN XY: 74506

African (AFR) AF: 0.00154 AC: 64 AN: 41588

American (AMR) AF: 0.00137 AC: 21 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

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

European-Finnish (FIN) AF: 0.0503 AC: 534 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00756 AC: 514 AN: 68024

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00594 Hom.: 0

Bravo AF: 0.00369

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00616

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.81
CADD	Benign	2.8
DANN	Benign	0.74
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61766284; hg19: chr1-949597;