chr22-17085104-C-T

Variant names:

• chr22-17085104-C-T
• rs1351337413
• NM_014339.7:c.13C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014339.7(IL17RA):​c.13C>T​(p.Arg5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,209,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: IL17RA NM_014339.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.87
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.087405056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL17RA	NM_014339.7	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 13	ENST00000319363.11	NP_055154.3
IL17RA	NM_001289905.2	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 12		NP_001276834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL17RA	ENST00000319363.11	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 13	1	NM_014339.7	ENSP00000320936.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000248 AC: 3 AN: 1209622 Hom.: 0 Cov.: 59 AF XY: 0.00000341 AC XY: 2 AN XY: 586964

African (AFR) AF: 0.00 AC: 0 AN: 24382

American (AMR) AF: 0.00 AC: 0 AN: 12514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17178

East Asian (EAS) AF: 0.00 AC: 0 AN: 27480

South Asian (SAS) AF: 0.00 AC: 0 AN: 53980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4830

European-Non Finnish (NFE) AF: 0.00000303 AC: 3 AN: 990398

Other (OTH) AF: 0.00 AC: 0 AN: 49544

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 51 Uncertain:1

Feb 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 5 of the IL17RA protein (p.Arg5Cys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with IL17RA-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.98	L;L
PhyloP100		-2.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.013
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.014	D;D
Polyphen		0.0020	B;.
Vest4		0.029
MutPred		0.30		Gain of catalytic residue at S9 (P = 0.0077);Gain of catalytic residue at S9 (P = 0.0077);
MVP		0.085
MPC		0.26
ClinPred		0.31	T
GERP RS		-0.32
PromoterAI		-0.067	Neutral
Varity_R		0.12
gMVP		0.58
Mutation Taster		=99/1	polymorphism

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: rs1351337413; hg19: chr22-17565994;