Genetic Variant ICOSLG:c.*1496A>G (chr21-44227538-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015259.6(ICOSLG):c.*1496A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000031 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ICOSLG
NM_015259.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.364

Publications

57 publications found

Variant links:

Genes affected

ICOSLG (HGNC:17087): (inducible T cell costimulator ligand) Enables identical protein binding activity. Predicted to be involved in T cell receptor signaling pathway and positive regulation of interleukin-4 production. Located in cytoplasmic ribonucleoprotein granule and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ICOSLG Gene-Disease associations (from GenCC):

combined immunodeficiency
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
immunodeficiency 119
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ICOSLG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICOSLG	NM_015259.6 link	c.*1496A>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000407780.8	NP_056074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICOSLG	ENST00000407780.8 link	c.*1496A>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_015259.6	ENSP00000384432.3

Frequencies

GnomAD3 genomes

AF:

0.0000306

AC:

AN:

65320

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000149

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

400858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

185714

African (AFR)

AF:

0.00

AC:

AN:

5222

American (AMR)

AF:

0.00

AC:

AN:

448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2914

East Asian (EAS)

AF:

0.00

AC:

AN:

2562

South Asian (SAS)

AF:

0.00

AC:

AN:

7136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

998

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

367758

Other (OTH)

AF:

0.00

AC:

AN:

13708

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000306

AC:

AN:

65344

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

31790

show subpopulations

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

African (AFR)

AF:

0.000148

AC:

AN:

13524

American (AMR)

AF:

0.00

AC:

AN:

6914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1886

East Asian (EAS)

AF:

0.00

AC:

AN:

3174

South Asian (SAS)

AF:

0.00

AC:

AN:

1874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

176

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

32436

Other (OTH)

AF:

0.00

AC:

AN:

966

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.695

Hom.:

105928

Asia WGS

AF:

0.678

AC:

2356

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.9

(source)

DANN

Benign

0.46

PhyloP100

-0.36

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over