rs4694637

Variant names:

• chr4-73747117-G-A
• rs4694637
• ENST00000401931.2:c.*5081G>A

Variant summary

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

The ENST00000401931.2(CXCL8):​c.*5081G>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 0.483 in 151,716 control chromosomes in the GnomAD database, including 19,108 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 0.48 (19108 hom., cov: 32)
• Consequence: CXCL8 ENST00000401931.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.59 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.*5081G>A		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000385908.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73223 AN: 151598 Hom.: 19102 Cov.: 32

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.499

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

GnomAD4 genome AF: 0.483 AC: 73258 AN: 151716 Hom.: 19108 Cov.: 32 AF XY: 0.490 AC XY: 36341 AN XY: 74122

African (AFR) AF: 0.259 AC: 10740 AN: 41388

American (AMR) AF: 0.597 AC: 9072 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2093 AN: 3470

East Asian (EAS) AF: 0.608 AC: 3123 AN: 5138

South Asian (SAS) AF: 0.606 AC: 2922 AN: 4822

European-Finnish (FIN) AF: 0.589 AC: 6235 AN: 10580

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

European-Non Finnish (NFE) AF: 0.550 AC: 37315 AN: 67822

Other (OTH) AF: 0.500 AC: 1052 AN: 2106

Alfa AF: 0.498 Hom.: 6190

Bravo AF: 0.471

Asia WGS AF: 0.599 AC: 2082 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.42
PhyloP100		0.36

Splicing

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

Other links and lift over

dbSNP: rs4694637; hg19: chr4-74612834;