22-17084966-C-G

Variant names:

• chr22-17084966-C-G
• rs562165706
• ENST00000477874.1:n.-126C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000477874.1(IL17RA):​n.-126C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,147,760 control chromosomes in the GnomAD database, including 6 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 0.0054 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: IL17RA ENST00000477874.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49
• Publications: 1 publications found

Genes affected

IL17RA (HGNC:5985): (interleukin 17 receptor A) Interleukin 17A (IL17A) is a proinflammatory cytokine secreted by activated T-lymphocytes. It is a potent inducer of the maturation of CD34-positive hematopoietic precursors into neutrophils. The transmembrane protein encoded by this gene (interleukin 17A receptor; IL17RA) is a ubiquitous type I membrane glycoprotein that binds with low affinity to interleukin 17A. Interleukin 17A and its receptor play a pathogenic role in many inflammatory and autoimmune diseases such as rheumatoid arthritis. Like other cytokine receptors, this receptor likely has a multimeric structure. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2014]

IL17RA Gene-Disease associations (from GenCC):

• immunodeficiency 51

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• chronic mucocutaneous candidiasis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00544 (828/152286) while in subpopulation AFR AF = 0.0188 (781/41578). AF 95% confidence interval is 0.0177. There are 5 homozygotes in GnomAd4. There are 381 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL17RA	NM_014339.7	c.-126C>G		upstream_gene_variant		ENST00000319363.11	NP_055154.3
IL17RA	NM_001289905.2	c.-126C>G		upstream_gene_variant			NP_001276834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL17RA	ENST00000319363.11	c.-126C>G		upstream_gene_variant		1	NM_014339.7	ENSP00000320936.6

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 819 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.000456 AC: 454 AN: 995474 Hom.: 1 Cov.: 14 AF XY: 0.000408 AC XY: 195 AN XY: 477580

African (AFR) AF: 0.0188 AC: 381 AN: 20300

American (AMR) AF: 0.00147 AC: 12 AN: 8172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14024

East Asian (EAS) AF: 0.00 AC: 0 AN: 25604

South Asian (SAS) AF: 0.0000351 AC: 1 AN: 28506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24570

Middle Eastern (MID) AF: 0.000239 AC: 1 AN: 4188

European-Non Finnish (NFE) AF: 0.0000121 AC: 10 AN: 828930

Other (OTH) AF: 0.00119 AC: 49 AN: 41180

GnomAD4 genome AF: 0.00544 AC: 828 AN: 152286 Hom.: 5 Cov.: 32 AF XY: 0.00512 AC XY: 381 AN XY: 74464

African (AFR) AF: 0.0188 AC: 781 AN: 41578

American (AMR) AF: 0.00203 AC: 31 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.00598

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 51 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.15
DANN	Benign	0.73
PhyloP100		-1.5
PromoterAI		0.036	Neutral

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: rs562165706; hg19: chr22-17565856;