4-122612665-C-T

Variant names:

• chr4-122612665-C-T
• rs17886348
• NM_021803.4:c.*45G>A

Variant summary

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

The NM_021803.4(IL21):​c.*45G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 1,330,264 control chromosomes in the GnomAD database, including 3,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (278 hom., cov: 32)
  • Exomes 𝑓: 0.066 (2922 hom.)
• Consequence: IL21 NM_021803.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.176
• Publications: 7 publications found

Genes affected

IL21 (HGNC:6005): (interleukin 21) This gene encodes a member of the common-gamma chain family of cytokines with immunoregulatory activity. The encoded protein plays a role in both the innate and adaptive immune responses by inducing the differentiation, proliferation and activity of multiple target cells including macrophages, natural killer cells, B cells and cytotoxic T cells. Dysregulation of this gene plays a role in multiple immune-mediated diseases including lupus, psoriasis and chronic inflammatory diseases. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

IL21 Gene-Disease associations (from GenCC):

• IL21-related infantile inflammatory bowel disease

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-122612665-C-T is Benign according to our data. Variant chr4-122612665-C-T is described in ClinVar as [Benign]. Clinvar id is 1269619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL21	NM_021803.4	c.*45G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000648588.1	NP_068575.1
IL21	NM_001207006.3	c.*162G>A		3_prime_UTR_variant	Exon 4 of 4		NP_001193935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL21	ENST00000648588.1	c.*45G>A		3_prime_UTR_variant	Exon 5 of 5		NM_021803.4	ENSP00000497915.1
IL21	ENST00000647784.1	n.386G>A		non_coding_transcript_exon_variant	Exon 4 of 4
IL21	ENST00000611104.2	c.*162G>A		downstream_gene_variant		1		ENSP00000477555.1

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7678 AN: 152034 Hom.: 278 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0978

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0752

Gnomad OTH AF: 0.0474

GnomAD2 exomes AF: 0.0524 AC: 12896 AN: 246312 AF XY: 0.0537

Gnomad AFR exome AF: 0.00891

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.0500

Gnomad EAS exome AF: 0.00196

Gnomad FIN exome AF: 0.0911

Gnomad NFE exome AF: 0.0724

Gnomad OTH exome AF: 0.0597

GnomAD4 exome AF: 0.0655 AC: 77209 AN: 1178112 Hom.: 2922 Cov.: 16 AF XY: 0.0649 AC XY: 38955 AN XY: 600354

African (AFR) AF: 0.00965 AC: 268 AN: 27774

American (AMR) AF: 0.0306 AC: 1350 AN: 44094

Ashkenazi Jewish (ASJ) AF: 0.0501 AC: 1218 AN: 24328

East Asian (EAS) AF: 0.00102 AC: 39 AN: 38262

South Asian (SAS) AF: 0.0344 AC: 2744 AN: 79878

European-Finnish (FIN) AF: 0.0877 AC: 4463 AN: 50886

Middle Eastern (MID) AF: 0.0551 AC: 288 AN: 5224

European-Non Finnish (NFE) AF: 0.0745 AC: 63866 AN: 856696

Other (OTH) AF: 0.0583 AC: 2973 AN: 50970

GnomAD4 genome AF: 0.0504 AC: 7672 AN: 152152 Hom.: 278 Cov.: 32 AF XY: 0.0510 AC XY: 3795 AN XY: 74392

African (AFR) AF: 0.0103 AC: 429 AN: 41514

American (AMR) AF: 0.0397 AC: 606 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3466

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5184

South Asian (SAS) AF: 0.0342 AC: 165 AN: 4826

European-Finnish (FIN) AF: 0.0978 AC: 1035 AN: 10586

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0752 AC: 5111 AN: 67980

Other (OTH) AF: 0.0460 AC: 97 AN: 2110

Alfa AF: 0.0661 Hom.: 421

Bravo AF: 0.0437

Asia WGS AF: 0.0160 AC: 55 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 20, 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	-0.84
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		0.18
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: rs17886348; hg19: chr4-123533820;