4-73740307-A-T

Variant names:

• chr4-73740307-A-T
• rs4073
• ENST00000401931.1:c.-352A>T

Variant summary

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

The ENST00000401931.1(CXCL8):​c.-352A>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 152,070 control chromosomes in the GnomAD database, including 18,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: 𝑓 0.47 (18466 hom., cov: 32)
• Consequence: CXCL8 ENST00000401931.1 upstream_gene
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.988

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 (EAS) allele frequency at 95% confidence interval = 0.591 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	ENST00000401931.1	c.-352A>T		upstream_gene_variant		1		ENSP00000385908.1
CXCL8	ENST00000696131.1	n.-352A>T		upstream_gene_variant				ENSP00000512424.1
CXCL8	ENST00000696132.1	n.-352A>T		upstream_gene_variant				ENSP00000512425.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 71000 AN: 151950 Hom.: 18462 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.483

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

GnomAD4 genome AF: 0.467 AC: 71028 AN: 152070 Hom.: 18466 Cov.: 32 AF XY: 0.475 AC XY: 35334 AN XY: 74336

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.588

Gnomad4 ASJ AF: 0.598

Gnomad4 EAS AF: 0.609

Gnomad4 SAS AF: 0.597

Gnomad4 FIN AF: 0.595

Gnomad4 NFE AF: 0.544

Gnomad4 OTH AF: 0.483

Alfa AF: 0.492 Hom.: 2449

Bravo AF: 0.453

Asia WGS AF: 0.589 AC: 2045 AN: 3474

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Cholangiocarcinoma Other:1

Dec 10, 2022

Department of Surgery, Campus Charité Mitte Campus Virchow-klinikum, Charite-Universitaetsmedizin Berlin

Significance: other

Review Status: no assertion criteria provided

Collection Method: research

T/T and T/A genotype associated with significantly shorter OS after surgical resection of intrahepatic CCA T/T and T/A genotype associated shorter overall survival

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.82

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4073; hg19: chr4-74606024;