4-73740952-T-G

Variant names:

• chr4-73740952-T-G
• rs2227307
• NM_000584.4:c.64+230T>G

Variant summary

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

The NM_000584.4(CXCL8):​c.64+230T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 151,958 control chromosomes in the GnomAD database, including 15,055 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 0.44 (15055 hom., cov: 32)
• Consequence: CXCL8 NM_000584.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.324
• Publications: 74 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 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.64+230T>G		intron	N/A	NP_000575.1
	CXCL8	NM_001354840.3		c.64+230T>G		intron	N/A	NP_001341769.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL8	ENST00000307407.8	TSL:1 MANE Select	c.64+230T>G		intron	N/A	ENSP00000306512.3
	CXCL8	ENST00000401931.2	TSL:1	c.64+230T>G		intron	N/A	ENSP00000385908.1
	CXCL8	ENST00000696131.1		n.*171T>G		non_coding_transcript_exon	Exon 1 of 4	ENSP00000512424.1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67395 AN: 151840 Hom.: 15050 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.439

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

GnomAD4 genome AF: 0.444 AC: 67446 AN: 151958 Hom.: 15055 Cov.: 32 AF XY: 0.438 AC XY: 32569 AN XY: 74286

African (AFR) AF: 0.492 AC: 20389 AN: 41438

American (AMR) AF: 0.368 AC: 5614 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1327 AN: 3468

East Asian (EAS) AF: 0.391 AC: 2016 AN: 5158

South Asian (SAS) AF: 0.378 AC: 1822 AN: 4820

European-Finnish (FIN) AF: 0.404 AC: 4262 AN: 10546

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30605 AN: 67956

Other (OTH) AF: 0.440 AC: 927 AN: 2108

Alfa AF: 0.453 Hom.: 2411

Bravo AF: 0.446

Asia WGS AF: 0.373 AC: 1296 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.60
PhyloP100		0.32
PromoterAI		0.0026	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2227307; hg19: chr4-74606669;