chr4-73743328-A-T

Position:

• chr4-73743328-A-T

Variant summary

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

The NM_000584.4(CXCL8):​c.*864A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 212,654 control chromosomes in the GnomAD database, including 13,021 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 0.32 (8709 hom., cov: 33)
  • Exomes 𝑓: 0.37 (4312 hom.)
• Consequence: CXCL8 NM_000584.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.135

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCL8	NM_000584.4	c.*864A>T		3_prime_UTR_variant	4/4	ENST00000307407.8	NP_000575.1
CXCL8	NM_001354840.3	c.*1292A>T		3_prime_UTR_variant	3/3		NP_001341769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCL8	ENST00000307407.8	c.*864A>T		3_prime_UTR_variant	4/4	1	NM_000584.4	ENSP00000306512.3

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47990 AN: 151724 Hom.: 8714 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.335

GnomAD4 exome AF: 0.368 AC: 22365 AN: 60812 Hom.: 4312 Cov.: 0 AF XY: 0.369 AC XY: 10396 AN XY: 28206

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.275

Gnomad4 ASJ exome AF: 0.344

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.408

Gnomad4 OTH exome AF: 0.370

GnomAD4 genome AF: 0.316 AC: 47990 AN: 151842 Hom.: 8709 Cov.: 33 AF XY: 0.312 AC XY: 23170 AN XY: 74250

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.345

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.336

Alfa AF: 0.272 Hom.: 869

Bravo AF: 0.305

Asia WGS AF: 0.323 AC: 1119 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.8
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1126647; hg19: chr4-74609045;