rs2243251

Variant names:

• chr5-132674095-A-G
• rs2243251
• NM_000589.4:c.45A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000589.4(IL4):​c.45A>G​(p.Leu15Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0093 in 1,614,072 control chromosomes in the GnomAD database, including 1,152 homozygotes. 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 0.048 (581 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (571 hom.)
• Consequence: IL4 NM_000589.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154
• Publications: 13 publications found

Genes affected

IL4 (HGNC:6014): (interleukin 4) The protein encoded by this gene is a pleiotropic cytokine produced by activated T cells. This cytokine is a ligand for interleukin 4 receptor. The interleukin 4 receptor also binds to IL13, which may contribute to many overlapping functions of this cytokine and IL13. STAT6, a signal transducer and activator of transcription, has been shown to play a central role in mediating the immune regulatory signal of this cytokine. This gene, IL3, IL5, IL13, and CSF2 form a cytokine gene cluster on chromosome 5q, with this gene particularly close to IL13. This gene, IL13 and IL5 are found to be regulated coordinately by several long-range regulatory elements in an over 120 kilobase range on the chromosome. IL4 is considered an important cytokine for tissue repair, counterbalancing the effects of proinflammatory type 1 cytokines, however, it also promotes allergic airway inflammation. Moreover, IL-4, a type 2 cytokine, mediates and regulates a variety of human host responses such as allergic, anti-parasitic, wound healing, and acute inflammation. This cytokine has been reported to promote resolution of neutrophil-mediated acute lung injury. In an allergic response, IL-4 has an essential role in the production of allergen-specific immunoglobin (Ig) E. This pro-inflammatory cytokine has been observed to be increased in COVID-19 (Coronavirus disease 2019) patients, but is not necessarily associated with severe COVID-19 pathology. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Aug 2020]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=-0.154 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4	NM_000589.4	c.45A>G	p.Leu15Leu	synonymous_variant	Exon 1 of 4	ENST00000231449.7	NP_000580.1
IL4	NM_172348.3	c.45A>G	p.Leu15Leu	synonymous_variant	Exon 1 of 3		NP_758858.1
IL4	NM_001354990.2	c.45A>G	p.Leu15Leu	synonymous_variant	Exon 1 of 5		NP_001341919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL4	ENST00000231449.7	c.45A>G	p.Leu15Leu	synonymous_variant	Exon 1 of 4	1	NM_000589.4	ENSP00000231449.2
IL4	ENST00000350025.2	c.45A>G	p.Leu15Leu	synonymous_variant	Exon 1 of 3	1		ENSP00000325190.3
IL4	ENST00000622422.1	c.45A>G	p.Leu15Leu	synonymous_variant	Exon 1 of 5	1		ENSP00000480581.1

Frequencies

GnomAD3 genomes AF: 0.0480 AC: 7307 AN: 152130 Hom.: 577 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0127 AC: 3195 AN: 251494 AF XY: 0.00920

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.00853

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000703

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00526 AC: 7682 AN: 1461824 Hom.: 571 Cov.: 31 AF XY: 0.00455 AC XY: 3311 AN XY: 727210

African (AFR) AF: 0.169 AC: 5658 AN: 33468

American (AMR) AF: 0.00979 AC: 438 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00137 AC: 118 AN: 86258

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53420

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5768

European-Non Finnish (NFE) AF: 0.000559 AC: 622 AN: 1111960

Other (OTH) AF: 0.0121 AC: 730 AN: 60390

GnomAD4 genome AF: 0.0482 AC: 7336 AN: 152248 Hom.: 581 Cov.: 32 AF XY: 0.0461 AC XY: 3431 AN XY: 74432

African (AFR) AF: 0.167 AC: 6919 AN: 41530

American (AMR) AF: 0.0190 AC: 290 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68020

Other (OTH) AF: 0.0350 AC: 74 AN: 2112

Alfa AF: 0.0194 Hom.: 355

Bravo AF: 0.0545

Asia WGS AF: 0.00982 AC: 35 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.51
PhyloP100		-0.15
PromoterAI		0.025	Neutral
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: rs2243251; hg19: chr5-132009787;