22-17085191-C-T

Variant names:

• chr22-17085191-C-T
• rs1387278734
• NM_014339.7:c.100C>T
• IL17RA p.Arg34*

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_014339.7(IL17RA):​c.100C>T​(p.Arg34*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,376,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R34R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: IL17RA NM_014339.7 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.305
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• chronic mucocutaneous candidiasis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014339.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL17RA	NM_014339.7	MANE Select	c.100C>T	p.Arg34*	stop_gained	Exon 1 of 13	NP_055154.3
	IL17RA	NM_001289905.2		c.100C>T	p.Arg34*	stop_gained	Exon 1 of 12	NP_001276834.1	Q96F46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL17RA	ENST00000319363.11	TSL:1 MANE Select	c.100C>T	p.Arg34*	stop_gained	Exon 1 of 13	ENSP00000320936.6	Q96F46-1
	IL17RA	ENST00000940705.1		c.100C>T	p.Arg34*	stop_gained	Exon 1 of 12	ENSP00000610764.1
	IL17RA	ENST00000612619.2	TSL:5	c.100C>T	p.Arg34*	stop_gained	Exon 1 of 12	ENSP00000479970.1	Q96F46-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1376158 Hom.: 0 Cov.: 59 AF XY: 0.00 AC XY: 0 AN XY: 678932

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29868

American (AMR) AF: 0.00 AC: 0 AN: 34828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24706

East Asian (EAS) AF: 0.00 AC: 0 AN: 34252

South Asian (SAS) AF: 0.00 AC: 0 AN: 77548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4884

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074624

Other (OTH) AF: 0.00 AC: 0 AN: 57408

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.051
FATHMM_MKL	Benign	0.54	D
PhyloP100		-0.30
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=2/198	disease causing (fs/PTC)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1387278734;

hg19: chr22-17566081;