rs2243279

Variant names:

• chr5-132680535-G-A
• rs2243279
• NM_000589.4:c.360+645G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000589.4(IL4):​c.360+645G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 152,274 control chromosomes in the GnomAD database, including 37 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 0.013 (37 hom., cov: 32)
• Consequence: IL4 NM_000589.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• Publications: 9 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]

LOC105379176 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (2014/152274) while in subpopulation AFR AF = 0.0458 (1903/41548). AF 95% confidence interval is 0.0441. There are 37 homozygotes in GnomAd4. There are 953 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2014 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4	NM_000589.4	c.360+645G>A		intron_variant	Intron 3 of 3	ENST00000231449.7	NP_000580.1
IL4	NM_172348.3	c.312+645G>A		intron_variant	Intron 2 of 2		NP_758858.1
IL4	NM_001354990.2	c.*50+645G>A		intron_variant	Intron 4 of 4		NP_001341919.1
LOC105379176	NR_134248.1	n.177-419C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL4	ENST00000231449.7	c.360+645G>A		intron_variant	Intron 3 of 3	1	NM_000589.4	ENSP00000231449.2
IL4	ENST00000350025.2	c.312+645G>A		intron_variant	Intron 2 of 2	1		ENSP00000325190.3
IL4	ENST00000622422.1	c.*50+645G>A		intron_variant	Intron 4 of 4	1		ENSP00000480581.1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2004 AN: 152156 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0115

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

GnomAD4 genome AF: 0.0132 AC: 2014 AN: 152274 Hom.: 37 Cov.: 32 AF XY: 0.0128 AC XY: 953 AN XY: 74452

African (AFR) AF: 0.0458 AC: 1903 AN: 41548

American (AMR) AF: 0.00438 AC: 67 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00590 Hom.: 19

Bravo AF: 0.0157

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.5
DANN	Benign	0.67
PhyloP100		1.6
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: rs2243279; hg19: chr5-132016227;