5-132682440-A-G

Variant names:

• chr5-132682440-A-G
• rs2243289
• NM_000589.4:c.361-46A>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.361-46A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,172,270 control chromosomes in the GnomAD database, including 33,787 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 0.23 (5451 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28336 hom.)
• Consequence: IL4 NM_000589.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 27 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.756 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.361-46A>G		intron	N/A	NP_000580.1
	IL4	NM_172348.3		c.313-46A>G		intron	N/A	NP_758858.1
	IL4	NM_001354990.2		c.*51-46A>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.361-46A>G		intron	N/A	ENSP00000231449.2
	IL4	ENST00000350025.2	TSL:1	c.313-46A>G		intron	N/A	ENSP00000325190.3
	IL4	ENST00000622422.1	TSL:1	c.*51-46A>G		intron	N/A	ENSP00000480581.1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35362 AN: 151894 Hom.: 5453 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.207

GnomAD2 exomes AF: 0.263 AC: 62899 AN: 238796 AF XY: 0.246

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.796

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.194 AC: 198411 AN: 1020258 Hom.: 28336 Cov.: 13 AF XY: 0.190 AC XY: 100179 AN XY: 526194

African (AFR) AF: 0.269 AC: 6670 AN: 24814

American (AMR) AF: 0.413 AC: 17211 AN: 41690

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 4337 AN: 22914

East Asian (EAS) AF: 0.738 AC: 27747 AN: 37608

South Asian (SAS) AF: 0.165 AC: 12336 AN: 74674

European-Finnish (FIN) AF: 0.343 AC: 18102 AN: 52712

Middle Eastern (MID) AF: 0.115 AC: 569 AN: 4930

European-Non Finnish (NFE) AF: 0.143 AC: 101963 AN: 715232

Other (OTH) AF: 0.207 AC: 9476 AN: 45684

GnomAD4 genome AF: 0.233 AC: 35390 AN: 152012 Hom.: 5451 Cov.: 32 AF XY: 0.244 AC XY: 18146 AN XY: 74260

African (AFR) AF: 0.263 AC: 10909 AN: 41438

American (AMR) AF: 0.295 AC: 4505 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 658 AN: 3472

East Asian (EAS) AF: 0.776 AC: 4008 AN: 5166

South Asian (SAS) AF: 0.191 AC: 920 AN: 4818

European-Finnish (FIN) AF: 0.358 AC: 3780 AN: 10550

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10115 AN: 67978

Other (OTH) AF: 0.209 AC: 443 AN: 2116

Alfa AF: 0.199 Hom.: 743

Bravo AF: 0.236

Asia WGS AF: 0.458 AC: 1591 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.43
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2243289; hg19: chr5-132018132; COSMIC: COSV51503577; COSMIC: COSV51503577;