rs2070874

chr5-132674018-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000589.4(IL4):c.-33C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,602,216 control chromosomes in the GnomAD database, including 42,660 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 0.28 (7669 hom., cov: 32)
  • Exomes 𝑓: 0.18 (34991 hom.)
• Consequence: IL4 NM_000589.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4	NM_000589.4	c.-33C>T		5_prime_UTR_variant	1/4	ENST00000231449.7
IL4	NM_001354990.2	c.-33C>T		5_prime_UTR_variant	1/5
IL4	NM_172348.3	c.-33C>T		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4	ENST00000231449.7	c.-33C>T		5_prime_UTR_variant	1/4	1	NM_000589.4	P1
IL4	ENST00000622422.1	c.-33C>T		5_prime_UTR_variant	1/5	1
IL4	ENST00000350025.2			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42143 AN: 151898 Hom.: 7661 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.240

GnomAD3 exomes AF: 0.276 AC: 69369 AN: 250924 Hom.: 14266 AF XY: 0.255 AC XY: 34617 AN XY: 135604

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.442

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.792

Gnomad SAS exome AF: 0.166

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.180 AC: 260836 AN: 1450200 Hom.: 34991 Cov.: 30 AF XY: 0.177 AC XY: 127785 AN XY: 721696

Gnomad4 AFR exome AF: 0.416

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.736

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.210

GnomAD4 genome AF: 0.278 AC: 42189 AN: 152016 Hom.: 7669 Cov.: 32 AF XY: 0.287 AC XY: 21329 AN XY: 74292

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.310

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.775

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.359

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.242

Alfa AF: 0.168 Hom.: 3121

Bravo AF: 0.287

Asia WGS AF: 0.462 AC: 1606 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	4.8
Dann	Benign	0.82

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: rs2070874; hg19: chr5-132009710;