rs3093363

Variant names:

• chr16-27443241-A-G
• rs3093363
• NM_181078.3:c.507+125A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181078.3(IL21R):​c.507+125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 788,610 control chromosomes in the GnomAD database, including 38,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9559 hom., cov: 30)
  • Exomes 𝑓: 0.29 (29310 hom.)
• Consequence: IL21R NM_181078.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.292
• Publications: 9 publications found

Genes affected

IL21R (HGNC:6006): (interleukin 21 receptor) The protein encoded by this gene is a cytokine receptor for interleukin 21 (IL21). It belongs to the type I cytokine receptors, and has been shown to form a heterodimeric receptor complex with the common gamma-chain, a receptor subunit also shared by the receptors for interleukin 2, 4, 7, 9, and 15. This receptor transduces the growth promoting signal of IL21, and is important for the proliferation and differentiation of T cells, B cells, and natural killer (NK) cells. The ligand binding of this receptor leads to the activation of multiple downstream signaling molecules, including JAK1, JAK3, STAT1, and STAT3. Knockout studies of a similar gene in mouse suggest a role for this gene in regulating immunoglobulin production. Three alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]

IL21R Gene-Disease associations (from GenCC):

• immunodeficiency disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cryptosporidiosis-chronic cholangitis-liver disease syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000308281 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-27443241-A-G is Benign according to our data. Variant chr16-27443241-A-G is described in ClinVar as [Benign]. Clinvar id is 1271815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL21R	NM_181078.3	c.507+125A>G		intron_variant	Intron 5 of 8	ENST00000337929.8	NP_851564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL21R	ENST00000337929.8	c.507+125A>G		intron_variant	Intron 5 of 8	1	NM_181078.3	ENSP00000338010.3

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52162 AN: 151736 Hom.: 9524 Cov.: 30

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.324

GnomAD4 exome AF: 0.290 AC: 184918 AN: 636756 Hom.: 29310 AF XY: 0.284 AC XY: 91902 AN XY: 323592

African (AFR) AF: 0.486 AC: 7199 AN: 14812

American (AMR) AF: 0.264 AC: 4101 AN: 15524

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 3760 AN: 13454

East Asian (EAS) AF: 0.124 AC: 3549 AN: 28618

South Asian (SAS) AF: 0.115 AC: 4509 AN: 39102

European-Finnish (FIN) AF: 0.331 AC: 12028 AN: 36304

Middle Eastern (MID) AF: 0.285 AC: 630 AN: 2210

European-Non Finnish (NFE) AF: 0.307 AC: 140073 AN: 455936

Other (OTH) AF: 0.294 AC: 9069 AN: 30796

GnomAD4 genome AF: 0.344 AC: 52234 AN: 151854 Hom.: 9559 Cov.: 30 AF XY: 0.344 AC XY: 25525 AN XY: 74222

African (AFR) AF: 0.480 AC: 19872 AN: 41370

American (AMR) AF: 0.294 AC: 4489 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 939 AN: 3466

East Asian (EAS) AF: 0.106 AC: 548 AN: 5154

South Asian (SAS) AF: 0.124 AC: 594 AN: 4808

European-Finnish (FIN) AF: 0.341 AC: 3605 AN: 10566

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21201 AN: 67914

Other (OTH) AF: 0.323 AC: 683 AN: 2112

Alfa AF: 0.316 Hom.: 30744

Bravo AF: 0.346

Asia WGS AF: 0.157 AC: 547 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.88
DANN	Benign	0.34
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3093363; hg19: chr16-27454562;