chr21-44227763-C-T

Variant names:

• chr21-44227763-C-T
• rs15927
• NM_015259.6:c.*1271G>A

Variant summary

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

The NM_001395918.1(ICOSLG):​c.*1767G>A 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 0.017 (7 hom., cov: 1)
  • Exomes 𝑓: 0.0059 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ICOSLG NM_001395918.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.495
• Publications: 12 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=-0.82).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	NM_015259.6	MANE Select	c.*1271G>A		3_prime_UTR	Exon 7 of 7	NP_056074.1
	ICOSLG	NM_001395918.1		c.*1767G>A		3_prime_UTR	Exon 7 of 7	NP_001382847.1
	ICOSLG	NM_001365759.2		c.*1271G>A		3_prime_UTR	Exon 7 of 7	NP_001352688.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICOSLG	ENST00000407780.8	TSL:1 MANE Select	c.*1271G>A		3_prime_UTR	Exon 7 of 7	ENSP00000384432.3
	ICOSLG	ENST00000400379.8	TSL:1	c.*1767G>A		3_prime_UTR	Exon 6 of 6	ENSP00000383230.3
	ICOSLG	ENST00000344330.9	TSL:1	c.898+2291G>A		intron	N/A	ENSP00000339477.4

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 598 AN: 35822 Hom.: 7 Cov.: 1

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00962

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.0434

Gnomad SAS AF: 0.0409

Gnomad FIN AF: 0.00407

Gnomad MID AF: 0.0246

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0236

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00586 AC: 283 AN: 48318 Hom.: 0 Cov.: 2 AF XY: 0.00601 AC XY: 138 AN XY: 22970

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

African (AFR) AF: 0.0183 AC: 8 AN: 438

American (AMR) AF: 0.00 AC: 0 AN: 48

Ashkenazi Jewish (ASJ) AF: 0.00500 AC: 2 AN: 400

East Asian (EAS) AF: 0.00505 AC: 2 AN: 396

South Asian (SAS) AF: 0.00808 AC: 7 AN: 866

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.00574 AC: 254 AN: 44262

Other (OTH) AF: 0.00522 AC: 9 AN: 1724

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0166 AC: 596 AN: 35864 Hom.: 7 Cov.: 1 AF XY: 0.0165 AC XY: 279 AN XY: 16866

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

African (AFR) AF: 0.0260 AC: 160 AN: 6158

American (AMR) AF: 0.0166 AC: 64 AN: 3844

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 21 AN: 1196

East Asian (EAS) AF: 0.0431 AC: 69 AN: 1600

South Asian (SAS) AF: 0.0395 AC: 33 AN: 836

European-Finnish (FIN) AF: 0.00407 AC: 9 AN: 2210

Middle Eastern (MID) AF: 0.0278 AC: 3 AN: 108

European-Non Finnish (NFE) AF: 0.0116 AC: 224 AN: 19240

Other (OTH) AF: 0.0237 AC: 11 AN: 464

⚠️ 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: 0.255 Hom.: 7319

Asia WGS AF: 0.448 AC: 1556 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.59
PhyloP100		-0.49
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: rs15927; hg19: chr21-45647646;