4-73740676-C-T

Position:

• chr4-73740676-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000584.4(CXCL8):​c.18C>T​(p.Ala6=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,578 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: CXCL8 NM_000584.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.25

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 4-73740676-C-T is Benign according to our data. Variant chr4-73740676-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 708667.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.25 with no splicing effect.
• BS2: High AC in GnomAd4 at 199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CXCL8	NM_000584.4	c.18C>T	p.Ala6=	synonymous_variant	1/4	ENST00000307407.8
CXCL8	NM_001354840.3	c.18C>T	p.Ala6=	synonymous_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CXCL8	ENST00000307407.8	c.18C>T	p.Ala6=	synonymous_variant	1/4	1	NM_000584.4	P1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00126 AC: 316 AN: 250850 Hom.: 1 AF XY: 0.00130 AC XY: 176 AN XY: 135588

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.00596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00160 AC: 2335 AN: 1461310 Hom.: 4 Cov.: 30 AF XY: 0.00164 AC XY: 1195 AN XY: 726982

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00616

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00176

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74438

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00137

EpiCase AF: 0.00120

EpiControl AF: 0.00173

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.99
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs1803205; hg19: chr4-74606393;