22-17109396-C-T

Position:

chr22-17109396-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014339.7(IL17RA):c.2177C>T(p.Ser726Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,796 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 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

IL17RA
NM_014339.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.832

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.039212823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL17RA	NM_014339.7 linkuse as main transcript	c.2177C>T	p.Ser726Leu	missense_variant	13/13	ENST00000319363.11	NP_055154.3	Q96F46-1
IL17RA	NM_001289905.2 linkuse as main transcript	c.2075C>T	p.Ser692Leu	missense_variant	12/12		NP_001276834.1	Q96F46-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL17RA	ENST00000319363.11 linkuse as main transcript	c.2177C>T	p.Ser726Leu	missense_variant	13/13	1	NM_014339.7	ENSP00000320936.6		Q96F46-1
IL17RA	ENST00000612619.2 linkuse as main transcript	c.2075C>T	p.Ser692Leu	missense_variant	12/12	5		ENSP00000479970.1		Q96F46-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000485

AC:

AN:

247554

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134786

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000108

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1460594

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726580

show subpopulations

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:

0.0000378

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 51

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 726 of the IL17RA protein (p.Ser726Leu). This variant is present in population databases (rs756332306, gnomAD 0.01%). 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: 340609). 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 leucine 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. -
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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.2177C>T (p.S726L) alteration is located in exon 13 (coding exon 13) of the IL17RA gene. This alteration results from a C to T substitution at nucleotide position 2177, causing the serine (S) at amino acid position 726 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.8

DANN

Benign

0.96

DEOGEN2

Benign

0.097

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.039

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.73

N;.

REVEL

Benign

0.0090

Sift

Benign

0.20

T;.

Sift4G

Benign

0.31

T;T

Polyphen

0.032

B;.

Vest4

0.033

MutPred

0.26

Gain of catalytic residue at S726 (P = 0.0028);.;

MVP

0.11

MPC

0.17

ClinPred

0.027

GERP RS

-0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.039

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over