rs2243251

Positions:

• chr5-132674095-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000589.4(IL4):​c.45A>G​(p.Leu15=) 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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
IL4	NM_000589.4	c.45A>G	p.Leu15=	synonymous_variant	1/4	ENST00000231449.7	NP_000580.1
IL4	NM_172348.3	c.45A>G	p.Leu15=	synonymous_variant	1/3		NP_758858.1
IL4	NM_001354990.2	c.45A>G	p.Leu15=	synonymous_variant	1/5		NP_001341919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL4	ENST00000231449.7	c.45A>G	p.Leu15=	synonymous_variant	1/4	1	NM_000589.4	ENSP00000231449	P1
IL4	ENST00000350025.2	c.45A>G	p.Leu15=	synonymous_variant	1/3	1		ENSP00000325190
IL4	ENST00000622422.1	c.45A>G	p.Leu15=	synonymous_variant	1/5	1		ENSP00000480581

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

GnomAD3 exomes AF: 0.0127 AC: 3195 AN: 251494 Hom.: 264 AF XY: 0.00920 AC XY: 1250 AN XY: 135922

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 SAS exome AF: 0.00140

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

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.00979

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.000559

Gnomad4 OTH exome AF: 0.0121

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

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0148 Hom.: 202

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2243251; hg19: chr5-132009787;