chr21-44227538-T-C

Variant names:

• chr21-44227538-T-C
• rs4819388
• NM_015259.6:c.*1496A>G

Variant summary

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

The NM_001395918.1(ICOSLG):​c.*1992A>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_001395918.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.364
• Publications: 57 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395918.1. 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
	ICOSLG	NM_015259.6	MANE Select	c.*1496A>G		3_prime_UTR	Exon 7 of 7	NP_056074.1
	ICOSLG	NM_001395918.1		c.*1992A>G		3_prime_UTR	Exon 7 of 7	NP_001382847.1
	ICOSLG	NM_001365759.2		c.*1496A>G		3_prime_UTR	Exon 7 of 7	NP_001352688.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.*1496A>G		3_prime_UTR	Exon 7 of 7	ENSP00000384432.3
	ICOSLG	ENST00000400379.8	TSL:1	c.*1992A>G		3_prime_UTR	Exon 6 of 6	ENSP00000383230.3
	ICOSLG	ENST00000344330.9	TSL:1	c.898+2516A>G		intron	N/A	ENSP00000339477.4

Frequencies

GnomAD3 genomes AF: 0.0000306 AC: 2 AN: 65320 Hom.: 0 Cov.: 0

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: 0 AN: 400858 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 185714

African (AFR) AF: 0.00 AC: 0 AN: 5222

American (AMR) AF: 0.00 AC: 0 AN: 448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2914

East Asian (EAS) AF: 0.00 AC: 0 AN: 2562

South Asian (SAS) AF: 0.00 AC: 0 AN: 7136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 998

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 367758

Other (OTH) AF: 0.00 AC: 0 AN: 13708

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000306 AC: 2 AN: 65344 Hom.: 0 Cov.: 0 AF XY: 0.0000315 AC XY: 1 AN XY: 31790

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

African (AFR) AF: 0.000148 AC: 2 AN: 13524

American (AMR) AF: 0.00 AC: 0 AN: 6914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1886

East Asian (EAS) AF: 0.00 AC: 0 AN: 3174

South Asian (SAS) AF: 0.00 AC: 0 AN: 1874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 176

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32436

Other (OTH) AF: 0.00 AC: 0 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.

Alfa AF: 0.695 Hom.: 105928

Asia WGS AF: 0.678 AC: 2356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.46
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

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: rs4819388; hg19: chr21-45647421;