NM_000589.4:c.184-2227C>G

Variant names:

• chr5-132677487-C-G
• rs2227282
• NM_000589.4:c.184-2227C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000589.4(IL4):​c.184-2227C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 152,122 control chromosomes in the GnomAD database, including 25,447 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 0.52 (25447 hom., cov: 32)
• Consequence: IL4 NM_000589.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.398
• Publications: 52 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4	NM_000589.4	c.184-2227C>G		intron_variant	Intron 2 of 3	ENST00000231449.7	NP_000580.1
IL4	NM_172348.3	c.136-2227C>G		intron_variant	Intron 1 of 2		NP_758858.1
IL4	NM_001354990.2	c.184-294C>G		intron_variant	Intron 2 of 4		NP_001341919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL4	ENST00000231449.7	c.184-2227C>G		intron_variant	Intron 2 of 3	1	NM_000589.4	ENSP00000231449.2
IL4	ENST00000350025.2	c.136-2227C>G		intron_variant	Intron 1 of 2	1		ENSP00000325190.3
IL4	ENST00000622422.1	c.184-294C>G		intron_variant	Intron 2 of 4	1		ENSP00000480581.1
IL4	ENST00000495905.1	n.150-2227C>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78344 AN: 152004 Hom.: 25451 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.564

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.515 AC: 78344 AN: 152122 Hom.: 25447 Cov.: 32 AF XY: 0.507 AC XY: 37735 AN XY: 74362

African (AFR) AF: 0.144 AC: 5988 AN: 41514

American (AMR) AF: 0.523 AC: 7992 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2313 AN: 3470

East Asian (EAS) AF: 0.159 AC: 823 AN: 5172

South Asian (SAS) AF: 0.644 AC: 3105 AN: 4822

European-Finnish (FIN) AF: 0.539 AC: 5694 AN: 10560

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.739 AC: 50235 AN: 67986

Other (OTH) AF: 0.563 AC: 1188 AN: 2112

Alfa AF: 0.604 Hom.: 3867

Bravo AF: 0.489

Asia WGS AF: 0.414 AC: 1440 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.39
PhyloP100		0.40
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: rs2227282; hg19: chr5-132013179; COSMIC: COSV51502842;