Genetic Variant NM_000589.4:c.-144C>A (chr5-132673907-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000589.4(IL4):c.-144C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 678,364 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

IL4
NM_000589.4 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.670

Publications

0 publications found

Variant links:

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]

IL4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IL4	NM_000589.4	MANE Select	c.-144C>A	upstream_gene	N/A	NP_000580.1	P05112-1
IL4	NM_172348.3		c.-144C>A	upstream_gene	N/A	NP_758858.1	Q5FC01
IL4	NM_001354990.2		c.-144C>A	upstream_gene	N/A	NP_001341919.1	U3LVN1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IL4	ENST00000231449.7	TSL:1 MANE Select	c.-144C>A	upstream_gene	N/A	ENSP00000231449.2	P05112-1
IL4	ENST00000350025.2	TSL:1	c.-144C>A	upstream_gene	N/A	ENSP00000325190.3	P05112-2
IL4	ENST00000622422.1	TSL:1	c.-144C>A	upstream_gene	N/A	ENSP00000480581.1	U3LVN1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000147

AC:

AN:

678364

Hom.:

AF XY:

0.00000286

AC XY:

AN XY:

349302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16798

American (AMR)

AF:

0.00

AC:

AN:

27160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15890

East Asian (EAS)

AF:

0.00

AC:

AN:

33742

South Asian (SAS)

AF:

0.0000199

AC:

AN:

50352

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3938

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

461674

Other (OTH)

AF:

0.00

AC:

AN:

33598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.3

(source)

DANN

Benign

0.73

PhyloP100

-0.67

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over