rs28376631

Positions:

• chr22-17109038-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000319363.11(IL17RA):​c.1819G>A​(p.Glu607Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,593,494 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E607G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 34)
  • Exomes 𝑓: 0.00083 (17 hom.)
• Consequence: IL17RA ENST00000319363.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003880918).
• BP6: Variant 22-17109038-G-A is Benign according to our data. Variant chr22-17109038-G-A is described in ClinVar as [Benign]. Clinvar id is 542922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17109038-G-A is described in Lovd as [Likely_benign]. Variant chr22-17109038-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00789 (1202/152352) while in subpopulation AFR AF= 0.0271 (1125/41588). AF 95% confidence interval is 0.0257. There are 17 homozygotes in gnomad4. There are 582 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL17RA	NM_014339.7	c.1819G>A	p.Glu607Lys	missense_variant	13/13	ENST00000319363.11	NP_055154.3
IL17RA	NM_001289905.2	c.1717G>A	p.Glu573Lys	missense_variant	12/12		NP_001276834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL17RA	ENST00000319363.11	c.1819G>A	p.Glu607Lys	missense_variant	13/13	1	NM_014339.7	ENSP00000320936	P2
IL17RA	ENST00000612619.2	c.1717G>A	p.Glu573Lys	missense_variant	12/12	5		ENSP00000479970	A2

Frequencies

GnomAD3 genomes AF: 0.00783 AC: 1192 AN: 152234 Hom.: 17 Cov.: 34

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00195 AC: 422 AN: 216528 Hom.: 7 AF XY: 0.00150 AC XY: 180 AN XY: 119716

Gnomad AFR exome AF: 0.0270

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000689

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000903

GnomAD4 exome AF: 0.000834 AC: 1202 AN: 1441142 Hom.: 17 Cov.: 44 AF XY: 0.000735 AC XY: 527 AN XY: 716908

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000822

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000847

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00789 AC: 1202 AN: 152352 Hom.: 17 Cov.: 34 AF XY: 0.00781 AC XY: 582 AN XY: 74504

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.000931 Hom.: 1

Bravo AF: 0.00909

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0213 AC: 93

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.00228 AC: 275

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Immunodeficiency 51 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.099
Sift	Benign	0.11	T;.
Sift4G	Benign	0.084	T;T
Polyphen		0.79	P;.
Vest4		0.078
MVP		0.30
MPC		0.24
ClinPred		0.033	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.52

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: rs28376631; hg19: chr22-17589928;