5-132677033-T-G

Variant names:

• chr5-132677033-T-G
• rs2227284
• NM_000589.4:c.183+2527T>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.183+2527T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 152,012 control chromosomes in the GnomAD database, including 25,526 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 (25526 hom., cov: 31)
• Consequence: IL4 NM_000589.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0150
• Publications: 97 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=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000589.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL4	NM_000589.4	MANE Select	c.183+2527T>G		intron	N/A	NP_000580.1
	IL4	NM_172348.3		c.136-2681T>G		intron	N/A	NP_758858.1
	IL4	NM_001354990.2		c.184-748T>G		intron	N/A	NP_001341919.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL4	ENST00000231449.7	TSL:1 MANE Select	c.183+2527T>G		intron	N/A	ENSP00000231449.2
	IL4	ENST00000350025.2	TSL:1	c.136-2681T>G		intron	N/A	ENSP00000325190.3
	IL4	ENST00000622422.1	TSL:1	c.184-748T>G		intron	N/A	ENSP00000480581.1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78827 AN: 151894 Hom.: 25530 Cov.: 31

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.567

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

GnomAD4 genome AF: 0.519 AC: 78824 AN: 152012 Hom.: 25526 Cov.: 31 AF XY: 0.511 AC XY: 37967 AN XY: 74284

African (AFR) AF: 0.156 AC: 6482 AN: 41478

American (AMR) AF: 0.524 AC: 8012 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2308 AN: 3466

East Asian (EAS) AF: 0.159 AC: 823 AN: 5164

South Asian (SAS) AF: 0.643 AC: 3095 AN: 4812

European-Finnish (FIN) AF: 0.539 AC: 5674 AN: 10530

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

European-Non Finnish (NFE) AF: 0.739 AC: 50227 AN: 67960

Other (OTH) AF: 0.566 AC: 1195 AN: 2112

Alfa AF: 0.481 Hom.: 3028

Bravo AF: 0.493

Asia WGS AF: 0.415 AC: 1444 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.5
DANN	Benign	0.85
PhyloP100		0.015
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: rs2227284; hg19: chr5-132012725; COSMIC: COSV51502838;