rs747892404

chr22-17109363-G-Achr22-17109363-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014339.7(IL17RA):c.2144G>A(p.Ser715Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,607,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: IL17RA NM_014339.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.725

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042806804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL17RA	NM_014339.7	c.2144G>A	p.Ser715Asn	missense_variant	13/13	ENST00000319363.11
IL17RA	NM_001289905.2	c.2042G>A	p.Ser681Asn	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL17RA	ENST00000319363.11	c.2144G>A	p.Ser715Asn	missense_variant	13/13	1	NM_014339.7	P2
IL17RA	ENST00000612619.2	c.2042G>A	p.Ser681Asn	missense_variant	12/12	5		A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000296 AC: 7 AN: 236468 Hom.: 0 AF XY: 0.0000308 AC XY: 4 AN XY: 129792

Gnomad AFR exome AF: 0.0000686

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000566

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000344 AC: 50 AN: 1455598 Hom.: 0 Cov.: 37 AF XY: 0.0000290 AC XY: 21 AN XY: 723962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000677 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 51 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 715 of the IL17RA protein (p.Ser715Asn). This variant is present in population databases (rs747892404, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with IL17RA-related conditions. ClinVar contains an entry for this variant (Variation ID: 574324). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IL17RA protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	7.0
Dann	Benign	0.94
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.81	N;.
REVEL	Benign	0.030
Sift	Benign	0.45	T;.
Sift4G	Benign	0.37	T;T
Polyphen		0.24	B;.
Vest4		0.024
MVP		0.088
MPC		0.19
ClinPred		0.025	T
GERP RS		-0.54
Varity_R		0.10
gMVP		0.20

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: rs747892404; hg19: chr22-17590253;