rs143600903

Positions:

• chr3-9928346-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1 PP5_Moderate BS2_Supporting

The NM_153460.4(IL17RC):​c.919C>T​(p.Gln307Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,604,316 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: IL17RC NM_153460.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.421

Genes affected

IL17RC (HGNC:18358): (interleukin 17 receptor C) This gene encodes a single-pass type I membrane protein that shares similarity with the interleukin-17 receptor (IL-17RA). Unlike IL-17RA, which is predominantly expressed in hemopoietic cells, and binds with high affinity to only IL-17A, this protein is expressed in nonhemopoietic tissues, and binds both IL-17A and IL-17F with similar affinities. The proinflammatory cytokines, IL-17A and IL-17F, have been implicated in the progression of inflammatory and autoimmune diseases. Multiple alternatively spliced transcript variants encoding different isoforms have been detected for this gene, and it has been proposed that soluble, secreted proteins lacking transmembrane and intracellular domains may function as extracellular antagonists to cytokine signaling. [provided by RefSeq, Feb 2011]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-9928346-C-T is Pathogenic according to our data. Variant chr3-9928346-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372245.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL17RC	NM_153460.4	c.919C>T	p.Gln307Ter	stop_gained	11/19	ENST00000403601.8	NP_703190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL17RC	ENST00000403601.8	c.919C>T	p.Gln307Ter	stop_gained	11/19	1	NM_153460.4	ENSP00000384969	P4

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152240 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000313

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: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000427 AC: 105 AN: 246170 Hom.: 1 AF XY: 0.000428 AC XY: 57 AN XY: 133330

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.000206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.000851

Gnomad NFE exome AF: 0.000638

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000319 AC: 463 AN: 1451958 Hom.: 2 Cov.: 37 AF XY: 0.000326 AC XY: 235 AN XY: 720722

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000318

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.000367

GnomAD4 genome AF: 0.000203 AC: 31 AN: 152358 Hom.: 0 Cov.: 34 AF XY: 0.000255 AC XY: 19 AN XY: 74510

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000561 AC: 68

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Candidiasis, familial, 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 06, 2015

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29128761, 28090315, Tepal2020[Case Report], 25918342, 33726816, 31980526, Simeoni2019[Other]) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.45	N
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.67
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs143600903; hg19: chr3-9970030;