rs4694178

Variant names:

• chr4-73746971-C-A
• rs4694178
• ENST00000401931.2:c.*4935C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000401931.2(CXCL8):​c.*4935C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 151,790 control chromosomes in the GnomAD database, including 18,629 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 0.47 (18629 hom., cov: 33)
• Consequence: CXCL8 ENST00000401931.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• Publications: 11 publications found

Genes affected

CXCL8 (HGNC:6025): (C-X-C motif chemokine ligand 8) The protein encoded by this gene is a member of the CXC chemokine family and is a major mediator of the inflammatory response. The encoded protein is commonly referred to as interleukin-8 (IL-8). IL-8 is secreted by mononuclear macrophages, neutrophils, eosinophils, T lymphocytes, epithelial cells, and fibroblasts. It functions as a chemotactic factor by guiding the neutrophils to the site of infection. Bacterial and viral products rapidly induce IL-8 expression. IL-8 also participates with other cytokines in the proinflammatory signaling cascade and plays a role in systemic inflammatory response syndrome (SIRS). This gene is believed to play a role in the pathogenesis of the lower respiratory tract infection bronchiolitis, a common respiratory tract disease caused by the respiratory syncytial virus (RSV). The overproduction of this proinflammatory protein is thought to cause the lung inflammation associated with csytic fibrosis. This proinflammatory protein is also suspected of playing a role in coronary artery disease and endothelial dysfunction. This protein is also secreted by tumor cells and promotes tumor migration, invasion, angiogenesis and metastasis. This chemokine is also a potent angiogenic factor. The binding of IL-8 to one of its receptors (IL-8RB/CXCR2) increases the permeability of blood vessels and increasing levels of IL-8 are positively correlated with increased severity of multiple disease outcomes (eg, sepsis). This gene and other members of the CXC chemokine gene family form a gene cluster in a region of chromosome 4q. [provided by RefSeq, May 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCL8	ENST00000401931.2	c.*4935C>A		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000385908.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71158 AN: 151672 Hom.: 18627 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.488

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

GnomAD4 genome AF: 0.469 AC: 71184 AN: 151790 Hom.: 18629 Cov.: 33 AF XY: 0.477 AC XY: 35375 AN XY: 74156

African (AFR) AF: 0.212 AC: 8806 AN: 41450

American (AMR) AF: 0.592 AC: 8988 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2090 AN: 3466

East Asian (EAS) AF: 0.606 AC: 3110 AN: 5128

South Asian (SAS) AF: 0.605 AC: 2920 AN: 4824

European-Finnish (FIN) AF: 0.590 AC: 6228 AN: 10562

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37305 AN: 67858

Other (OTH) AF: 0.489 AC: 1031 AN: 2108

Alfa AF: 0.486 Hom.: 2509

Bravo AF: 0.455

Asia WGS AF: 0.596 AC: 2072 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.4
DANN	Benign	0.68
PhyloP100		0.30

Splicing

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

Other links and lift over

dbSNP: rs4694178; hg19: chr4-74612688;