rs775839180

chr22-17103543-G-Achr22-17103543-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_014339.7(IL17RA):c.812G>A(p.Arg271His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,506 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: IL17RA NM_014339.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -2.46

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044011682).
• BP6: Variant 22-17103543-G-A is Benign according to our data. Variant chr22-17103543-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 340580.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000438 (64/1461384) while in subpopulation MID AF= 0.00208 (12/5768). AF 95% confidence interval is 0.0012. There are 0 homozygotes in gnomad4_exome. There are 38 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL17RA	NM_014339.7	c.812G>A	p.Arg271His	missense_variant	8/13	ENST00000319363.11
IL17RA	NM_001289905.2	c.812G>A	p.Arg271His	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL17RA	ENST00000319363.11	c.812G>A	p.Arg271His	missense_variant	8/13	1	NM_014339.7	P2
IL17RA	ENST00000612619.2	c.812G>A	p.Arg271His	missense_variant	8/12	5		A2
IL17RA	ENST00000694951.1	n.770G>A		non_coding_transcript_exon_variant	6/7
IL17RA	ENST00000694950.1	c.*317G>A		3_prime_UTR_variant, NMD_transcript_variant	7/7

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000560 AC: 14 AN: 250164 Hom.: 0 AF XY: 0.0000739 AC XY: 10 AN XY: 135326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000985

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461384 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 726962

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152122 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74322

Gnomad4 AFR AF: 0.0000484

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: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000763 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency 51 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 05, 2022	This variant is present in population databases (rs775839180, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 271 of the IL17RA protein (p.Arg271His). 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: 340580). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.059
Dann	Benign	0.88
DEOGEN2	Benign	0.060	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.12	N;.
REVEL	Benign	0.023
Sift	Benign	0.14	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.0	B;.
Vest4		0.090
MVP		0.10
MPC		0.24
ClinPred		0.038	T
GERP RS		-11
Varity_R		0.052
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs775839180; hg19: chr22-17584433; COSMIC: COSV100083476; COSMIC: COSV100083476;