rs2243290

Positions:

• chr5-132682477-C-A

Variant summary

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

The NM_000589.4(IL4):​c.361-9C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,546,350 control chromosomes in the GnomAD database, including 40,101 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 0.26 (6585 hom., cov: 32)
  • Exomes 𝑓: 0.18 (33516 hom.)
• Consequence: IL4 NM_000589.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002755
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL4	NM_000589.4	c.361-9C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000231449.7	NP_000580.1
LOC105379176	NR_134248.1	n.153G>T		non_coding_transcript_exon_variant	1/2
IL4	NM_001354990.2	c.*51-9C>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001341919.1
IL4	NM_172348.3	c.313-9C>A		splice_polypyrimidine_tract_variant, intron_variant			NP_758858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL4	ENST00000231449.7	c.361-9C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000589.4	ENSP00000231449	P1
IL4	ENST00000350025.2	c.313-9C>A		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000325190
IL4	ENST00000622422.1	c.*51-9C>A		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000480581

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39083 AN: 151906 Hom.: 6582 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.229

GnomAD3 exomes AF: 0.269 AC: 66627 AN: 247594 Hom.: 13396 AF XY: 0.250 AC XY: 33440 AN XY: 133704

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.433

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.795

Gnomad SAS exome AF: 0.167

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.181 AC: 252305 AN: 1394326 Hom.: 33516 Cov.: 22 AF XY: 0.178 AC XY: 124257 AN XY: 697388

Gnomad4 AFR exome AF: 0.353

Gnomad4 AMR exome AF: 0.417

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.739

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.257 AC: 39121 AN: 152024 Hom.: 6585 Cov.: 32 AF XY: 0.267 AC XY: 19873 AN XY: 74294

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.776

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.232

Alfa AF: 0.168 Hom.: 4268

Bravo AF: 0.264

Asia WGS AF: 0.467 AC: 1623 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0028
dbscSNV1_RF	Benign	0.23
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: rs2243290; hg19: chr5-132018169; COSMIC: COSV51503592; COSMIC: COSV51503592;