4-122612707-T-G

Variant names:

• chr4-122612707-T-G
• rs117127666
• NM_021803.4:c.*3A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021803.4(IL21):​c.*3A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,600,320 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (32 hom.)
• Consequence: IL21 NM_021803.4 3_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.381
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-122612707-T-G is Benign according to our data. Variant chr4-122612707-T-G is described in ClinVar as [Benign]. Clinvar id is 3055532.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00253 (386/152294) while in subpopulation EAS AF = 0.0249 (129/5182). AF 95% confidence interval is 0.0214. There are 2 homozygotes in GnomAd4. There are 235 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL21	NM_021803.4	c.*3A>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000648588.1	NP_068575.1
IL21	NM_001207006.3	c.*120A>C		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.*3A>C		3_prime_UTR_variant	Exon 5 of 5		NM_021803.4	ENSP00000497915.1
IL21	ENST00000647784.1	n.344A>C		non_coding_transcript_exon_variant	Exon 4 of 4
IL21	ENST00000611104.2	c.*120A>C		downstream_gene_variant		1		ENSP00000477555.1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 152176 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00395 AC: 989 AN: 250506 AF XY: 0.00396

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0238

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.000459

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00170 AC: 2465 AN: 1448026 Hom.: 32 Cov.: 28 AF XY: 0.00186 AC XY: 1345 AN XY: 721504

African (AFR) AF: 0.000181 AC: 6 AN: 33200

American (AMR) AF: 0.000157 AC: 7 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000461 AC: 12 AN: 26030

East Asian (EAS) AF: 0.0163 AC: 645 AN: 39558

South Asian (SAS) AF: 0.00595 AC: 512 AN: 85982

European-Finnish (FIN) AF: 0.0131 AC: 695 AN: 52986

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5744

European-Non Finnish (NFE) AF: 0.000318 AC: 350 AN: 1099884

Other (OTH) AF: 0.00384 AC: 230 AN: 59938

GnomAD4 genome AF: 0.00253 AC: 386 AN: 152294 Hom.: 2 Cov.: 32 AF XY: 0.00316 AC XY: 235 AN XY: 74470

African (AFR) AF: 0.000385 AC: 16 AN: 41572

American (AMR) AF: 0.00131 AC: 20 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5182

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4828

European-Finnish (FIN) AF: 0.0143 AC: 152 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68016

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.000706 Hom.: 1

Bravo AF: 0.00133

Asia WGS AF: 0.0140 AC: 49 AN: 3476

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

IL21-related disorder Benign:1

Sep 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.7
DANN	Benign	0.72
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

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: rs117127666; hg19: chr4-123533862; COSMIC: COSV52647390;