4-73743328-A-T

Variant names:

• chr4-73743328-A-T
• rs1126647
• NM_000584.4:c.*864A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 57 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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000584.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL8	NM_000584.4	MANE Select	c.*864A>T		3_prime_UTR	Exon 4 of 4	NP_000575.1
	CXCL8	NM_001354840.3		c.*1292A>T		3_prime_UTR	Exon 3 of 3	NP_001341769.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL8	ENST00000307407.8	TSL:1 MANE Select	c.*864A>T		3_prime_UTR	Exon 4 of 4	ENSP00000306512.3
	CXCL8	ENST00000401931.2	TSL:1	c.*1292A>T		3_prime_UTR	Exon 3 of 3	ENSP00000385908.1
	CXCL8	ENST00000696131.1		n.*1368A>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000512424.1

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

African (AFR) AF: 0.130 AC: 380 AN: 2922

American (AMR) AF: 0.275 AC: 518 AN: 1884

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1338 AN: 3890

East Asian (EAS) AF: 0.305 AC: 2678 AN: 8770

South Asian (SAS) AF: 0.337 AC: 175 AN: 520

European-Finnish (FIN) AF: 0.261 AC: 12 AN: 46

Middle Eastern (MID) AF: 0.363 AC: 135 AN: 372

European-Non Finnish (NFE) AF: 0.408 AC: 15244 AN: 37320

Other (OTH) AF: 0.370 AC: 1885 AN: 5088

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

African (AFR) AF: 0.132 AC: 5471 AN: 41472

American (AMR) AF: 0.295 AC: 4488 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1195 AN: 3462

East Asian (EAS) AF: 0.370 AC: 1904 AN: 5150

South Asian (SAS) AF: 0.346 AC: 1670 AN: 4830

European-Finnish (FIN) AF: 0.370 AC: 3900 AN: 10542

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.415 AC: 28189 AN: 67846

Other (OTH) AF: 0.336 AC: 710 AN: 2110

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.8
DANN	Benign	0.79
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1126647; hg19: chr4-74609045;