rs140221307

Positions:

• chr22-17105867-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_014339.7(IL17RA):​c.958T>C​(p.Trp320Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00389 in 1,613,944 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (19 hom.)
• Consequence: IL17RA NM_014339.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.70

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0836069).
• BP6: Variant 22-17105867-T-C is Benign according to our data. Variant chr22-17105867-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 340587.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00233 (355/152318) while in subpopulation NFE AF= 0.00457 (311/68026). AF 95% confidence interval is 0.00415. There are 0 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL17RA	NM_014339.7	c.958T>C	p.Trp320Arg	missense_variant	11/13	ENST00000319363.11	NP_055154.3
IL17RA	NM_001289905.2	c.943+265T>C		intron_variant			NP_001276834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL17RA	ENST00000319363.11	c.958T>C	p.Trp320Arg	missense_variant	11/13	1	NM_014339.7	ENSP00000320936.6
IL17RA	ENST00000612619.2	c.943+265T>C		intron_variant		5		ENSP00000479970.1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00173 AC: 435 AN: 251206 Hom.: 0 AF XY: 0.00170 AC XY: 231 AN XY: 135808

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00405 AC: 5917 AN: 1461626 Hom.: 19 Cov.: 33 AF XY: 0.00386 AC XY: 2806 AN XY: 727132

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00496

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00223 AC XY: 166 AN XY: 74480

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00457

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00327 Hom.: 4

Bravo AF: 0.00259

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00180 AC: 219

EpiCase AF: 0.00480

EpiControl AF: 0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency 51 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	IL17RA NM_014339.6 exon 11 p.Trp320Arg (c.958T>C): This variant has been reported in the literature in 1 individual with sarcoidosis, segregating with disease in 2 affected family members; of note, additional variants were identified in this family that the authors believed were suggestive of disease (Besnard 2018 PMID:29554915). This variant is present in 0.3% (443/129026) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/22-17586757-T-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:340587). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Familial Candidiasis, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

IL17RA-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2024

The IL17RA c.958T>C variant is predicted to result in the amino acid substitution p.Trp320Arg. This variant has been reported in the heterozygous state in individuals with sarcoidosis (Besnard et al. 2018. PubMed ID: 29554915). Of note, all of those individuals also had variants in other genes in additional to the IL17RA c.958T>C variant. This variant is reported in 0.34% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.46		Loss of helix (P = 0.0558);
MVP		0.27
MPC		1.0
ClinPred		0.063	T
GERP RS		5.2
Varity_R		0.55
gMVP		0.67

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: rs140221307; hg19: chr22-17586757; COSMIC: COSV100083554;