22-17085111-C-T

Variant summary

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

The NM_014339.7(IL17RA):c.20C>T(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 1,374,558 control chromosomes in the GnomAD database, including 32 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (29 hom.)
• Consequence: IL17RA NM_014339.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0290

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=0.0030026138).
• BP6: Variant 22-17085111-C-T is Benign according to our data. Variant chr22-17085111-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 340562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17085111-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00378 (576/152248) while in subpopulation NFE AF= 0.00606 (412/67990). AF 95% confidence interval is 0.00558. There are 3 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL17RA	NM_014339.7	c.20C>T	p.Pro7Leu	missense_variant	1/13	ENST00000319363.11
IL17RA	NM_001289905.2	c.20C>T	p.Pro7Leu	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL17RA	ENST00000319363.11	c.20C>T	p.Pro7Leu	missense_variant	1/13	1	NM_014339.7	P2

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 577 AN: 152138 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00606

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00588 AC: 164 AN: 27870 Hom.: 1 AF XY: 0.00629 AC XY: 108 AN XY: 17162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00340

Gnomad FIN exome AF: 0.00639

Gnomad NFE exome AF: 0.00968

Gnomad OTH exome AF: 0.00605

GnomAD4 exome AF: 0.00618 AC: 7554 AN: 1222310 Hom.: 29 Cov.: 59 AF XY: 0.00614 AC XY: 3648 AN XY: 594516

Gnomad4 AFR exome AF: 0.000690

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00128

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00245

Gnomad4 FIN exome AF: 0.00183

Gnomad4 NFE exome AF: 0.00705

Gnomad4 OTH exome AF: 0.00453

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152248 Hom.: 3 Cov.: 33 AF XY: 0.00357 AC XY: 266 AN XY: 74446

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00606

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00219 Hom.: 0

Bravo AF: 0.00417

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00701 AC: 27

ExAC AF: 0.00149 AC: 65

ClinVar

Significance: Likely 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial Candidiasis, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Immunodeficiency 51 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

IL17RA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	5.8
Dann	Benign	0.80
DEOGEN2	Benign	0.060	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.060	N;.
REVEL	Benign	0.0070
Sift	Benign	0.68	T;.
Sift4G	Benign	0.77	T;T
Polyphen		0.27	B;.
Vest4		0.076
MVP		0.12
MPC		0.19
ClinPred		0.0058	T
GERP RS		-0.092
Varity_R		0.022
gMVP		0.46

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: rs143652002; hg19: chr22-17566001; COSMIC: COSV60055527; COSMIC: COSV60055527;