22-17085110-C-T

Variant names:

• chr22-17085110-C-T
• rs534399492
• NM_014339.7:c.19C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_014339.7(IL17RA):​c.19C>T​(p.Pro7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,373,346 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. P7L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: IL17RA NM_014339.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.981
• Publications: 3 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045977235).
• BP6: Variant 22-17085110-C-T is Benign according to our data. Variant chr22-17085110-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 714587.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00184 (280/152264) while in subpopulation AFR AF = 0.0065 (270/41568). AF 95% confidence interval is 0.00586. There are 1 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL17RA	NM_014339.7	c.19C>T	p.Pro7Ser	missense_variant	Exon 1 of 13	ENST00000319363.11	NP_055154.3
IL17RA	NM_001289905.2	c.19C>T	p.Pro7Ser	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.19C>T	p.Pro7Ser	missense_variant	Exon 1 of 13	1	NM_014339.7	ENSP00000320936.6

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152154 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000478

GnomAD2 exomes AF: 0.000150 AC: 4 AN: 26720 AF XY: 0.000122

Gnomad AFR exome AF: 0.00652

Gnomad AMR exome AF: 0.000230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000173 AC: 211 AN: 1221082 Hom.: 1 Cov.: 60 AF XY: 0.000158 AC XY: 94 AN XY: 593700

African (AFR) AF: 0.00792 AC: 195 AN: 24632

American (AMR) AF: 0.000290 AC: 4 AN: 13776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17878

East Asian (EAS) AF: 0.00 AC: 0 AN: 27572

South Asian (SAS) AF: 0.00 AC: 0 AN: 56360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30008

Middle Eastern (MID) AF: 0.000206 AC: 1 AN: 4846

European-Non Finnish (NFE) AF: 0.00000201 AC: 2 AN: 995936

Other (OTH) AF: 0.000180 AC: 9 AN: 50074

GnomAD4 genome AF: 0.00184 AC: 280 AN: 152264 Hom.: 1 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74446

African (AFR) AF: 0.00650 AC: 270 AN: 41568

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000487 Hom.: 0

Bravo AF: 0.00222

ExAC AF: 0.0000464 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency 51 Benign:2

Jul 25, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Feb 12, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.12
DANN	Benign	0.82
DEOGEN2	Benign	0.065	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		-0.98
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.15	N;.
REVEL	Benign	0.011
Sift	Benign	0.70	T;.
Sift4G	Benign	0.73	T;T
Polyphen		0.12	B;.
Vest4		0.062
MVP		0.061
MPC		0.19
ClinPred		0.0038	T
GERP RS		-7.0
PromoterAI		0.029	Neutral
Varity_R		0.016
gMVP		0.51
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: rs534399492; hg19: chr22-17566000;