rs148575246

chr3-9932859-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 6P and 12B. PVS1_Moderate PP3_Strong BP6_Very_Strong BS2

The NM_153460.4(IL17RC):c.1522+1G>C variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,573,836 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (5 hom., cov: 33)
  • Exomes 𝑓: 0.011 (113 hom.)
• Consequence: IL17RC NM_153460.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.10

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_benign. Variant got -6 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.017568192 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 3-9932859-G-C is Benign according to our data. Variant chr3-9932859-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 542537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL17RC	NM_153460.4	c.1522+1G>C		splice_donor_variant		ENST00000403601.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL17RC	ENST00000403601.8	c.1522+1G>C		splice_donor_variant		1	NM_153460.4	P4

Frequencies

GnomAD3 genomes AF: 0.00750 AC: 1142 AN: 152232 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00630 AC: 1285 AN: 204104 Hom.: 9 AF XY: 0.00625 AC XY: 701 AN XY: 112080

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00460

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.0111 AC: 15768 AN: 1421486 Hom.: 113 Cov.: 33 AF XY: 0.0108 AC XY: 7590 AN XY: 705180

Gnomad4 AFR exome AF: 0.00211

Gnomad4 AMR exome AF: 0.00450

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00190

Gnomad4 FIN exome AF: 0.00463

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00749 AC: 1141 AN: 152350 Hom.: 5 Cov.: 33 AF XY: 0.00656 AC XY: 489 AN XY: 74502

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00724 Hom.: 0

Bravo AF: 0.00713

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00300 AC: 12

ESP6500EA AF: 0.00756 AC: 62

ExAC AF: 0.00573 AC: 689

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Candidiasis, familial, 9 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 12, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

IL17RC: BS1, BS2 -

IL17RC-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Benign	0.63	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148575246; hg19: chr3-9974543;