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GeneBe

1-1014217-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_005101.4(ISG15):c.237C>T(p.Asp79=) 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

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.32
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-1014217-C-T is Benign according to our data. Variant chr1-1014217-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.32 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ISG15NM_005101.4 linkuse as main transcriptc.237C>T p.Asp79= synonymous_variant 2/2 ENST00000649529.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ISG15ENST00000649529.1 linkuse as main transcriptc.237C>T p.Asp79= synonymous_variant 2/2 NM_005101.4 P1
ISG15ENST00000624697.4 linkuse as main transcriptc.213C>T p.Asp71= synonymous_variant 3/33
ISG15ENST00000624652.1 linkuse as main transcriptc.213C>T p.Asp71= synonymous_variant 3/33

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00751
AC:
1144
AN:
152236
Hom.:
22
Cov.:
35
show subpopulations
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
GnomAD3 exomes
AF:
0.00852
AC:
2130
AN:
250062
Hom.:
35
AF XY:
0.00830
AC XY:
1125
AN XY:
135510
show subpopulations
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 SAS exome
AF:
0.000131
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
show subpopulations
Gnomad4 AFR exome
AF:
0.00125
Gnomad4 AMR exome
AF:
0.00145
Gnomad4 ASJ exome
AF:
0.000306
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.0461
Gnomad4 NFE exome
AF:
0.00695
Gnomad4 OTH exome
AF:
0.00522
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00751
AC:
1144
AN:
152354
Hom.:
22
Cov.:
35
AF XY:
0.00942
AC XY:
702
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00154
Gnomad4 AMR
AF:
0.00137
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0503
Gnomad4 NFE
AF:
0.00756
Gnomad4 OTH
AF:
0.00379
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

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2021- -
Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
Cadd
Benign
2.8
Dann
Benign
0.74

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61766284; hg19: chr1-949597; API