rs3819025

Positions:

• chr6-52186476-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002190.3(IL17A):​c.27+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,612,372 control chromosomes in the GnomAD database, including 9,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1118 hom., cov: 33)
  • Exomes 𝑓: 0.072 (8168 hom.)
• Consequence: IL17A NM_002190.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.868

Genes affected

IL17A (HGNC:5981): (interleukin 17A) This gene is a member of the IL-17 receptor family which includes five members (IL-17RA-E) and the encoded protein is a proinflammatory cytokine produced by activated T cells. IL-17A-mediated downstream pathways induce the production of inflammatory molecules, chemokines, antimicrobial peptides, and remodeling proteins. The encoded protein elicits crucial impacts on host defense, cell trafficking, immune modulation, and tissue repair, with a key role in the induction of innate immune defenses. This cytokine stimulates non-hematopoietic cells and promotes chemokine production thereby attracting myeloid cells to inflammatory sites. This cytokine also regulates the activities of NF-kappaB and mitogen-activated protein kinases and can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO). IL-17A plays a pivotal role in various infectious diseases, inflammatory and autoimmune disorders, and cancer. High levels of this cytokine are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis. The lung damage induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is to a large extent, a result of the inflammatory response promoted by cytokines such as IL17A. [provided by RefSeq, Sep 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-52186476-G-A is Benign according to our data. Variant chr6-52186476-G-A is described in ClinVar as [Benign]. Clinvar id is 1273159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL17A	NM_002190.3	c.27+18G>A		intron_variant		ENST00000648244.1	NP_002181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL17A	ENST00000648244.1	c.27+18G>A		intron_variant			NM_002190.3	ENSP00000497968	P1

Frequencies

GnomAD3 genomes AF: 0.0889 AC: 13520 AN: 152154 Hom.: 1105 Cov.: 33

Gnomad AFR AF: 0.0752

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0503

Gnomad OTH AF: 0.0903

GnomAD3 exomes AF: 0.128 AC: 32108 AN: 250576 Hom.: 4518 AF XY: 0.117 AC XY: 15805 AN XY: 135416

Gnomad AFR exome AF: 0.0741

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.0533

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.0286

Gnomad NFE exome AF: 0.0516

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.0720 AC: 105093 AN: 1460100 Hom.: 8168 Cov.: 30 AF XY: 0.0730 AC XY: 53021 AN XY: 726376

Gnomad4 AFR exome AF: 0.0733

Gnomad4 AMR exome AF: 0.414

Gnomad4 ASJ exome AF: 0.0574

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.0296

Gnomad4 NFE exome AF: 0.0483

Gnomad4 OTH exome AF: 0.0787

GnomAD4 genome AF: 0.0890 AC: 13558 AN: 152272 Hom.: 1118 Cov.: 33 AF XY: 0.0936 AC XY: 6968 AN XY: 74448

Gnomad4 AFR AF: 0.0751

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.0519

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.0288

Gnomad4 NFE AF: 0.0503

Gnomad4 OTH AF: 0.0974

Alfa AF: 0.0700 Hom.: 1049

Bravo AF: 0.107

Asia WGS AF: 0.215 AC: 748 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 56. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.91
DANN	Benign	0.76

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: rs3819025; hg19: chr6-52051274; COSMIC: COSV60684508;