rs3819025

Variant names:

• chr6-52186476-G-A
• rs3819025
• NM_002190.3:c.27+18G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 78 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
IL17A	NM_002190.3	c.27+18G>A		intron_variant	Intron 1 of 2	ENST00000648244.1	NP_002181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL17A	ENST00000648244.1	c.27+18G>A		intron_variant	Intron 1 of 2		NM_002190.3	ENSP00000497968.1

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

GnomAD2 exomes AF: 0.128 AC: 32108 AN: 250576 AF XY: 0.117

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 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

African (AFR) AF: 0.0733 AC: 2450 AN: 33440

American (AMR) AF: 0.414 AC: 18468 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0574 AC: 1499 AN: 26118

East Asian (EAS) AF: 0.218 AC: 8620 AN: 39586

South Asian (SAS) AF: 0.156 AC: 13456 AN: 86096

European-Finnish (FIN) AF: 0.0296 AC: 1583 AN: 53394

Middle Eastern (MID) AF: 0.101 AC: 582 AN: 5764

European-Non Finnish (NFE) AF: 0.0483 AC: 53688 AN: 1110724

Other (OTH) AF: 0.0787 AC: 4747 AN: 60332

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

African (AFR) AF: 0.0751 AC: 3122 AN: 41560

American (AMR) AF: 0.286 AC: 4366 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3468

East Asian (EAS) AF: 0.196 AC: 1016 AN: 5174

South Asian (SAS) AF: 0.176 AC: 851 AN: 4822

European-Finnish (FIN) AF: 0.0288 AC: 306 AN: 10614

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0503 AC: 3425 AN: 68036

Other (OTH) AF: 0.0974 AC: 206 AN: 2114

Alfa AF: 0.0723 Hom.: 1662

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

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.91
DANN	Benign	0.76
PhyloP100		-0.87
PromoterAI		-0.019	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: rs3819025; hg19: chr6-52051274; COSMIC: COSV60684508;