rs143412184

chr3-9918069-G-Achr3-9918069-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_153460.4(IL17RC):c.274G>A(p.Val92Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,576,478 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts 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. V92L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: IL17RC NM_153460.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.41

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057941675).
• BP6: Variant 3-9918069-G-A is Benign according to our data. Variant chr3-9918069-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542544.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL17RC	NM_153460.4	c.274G>A	p.Val92Met	missense_variant	3/19	ENST00000403601.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL17RC	ENST00000403601.8	c.274G>A	p.Val92Met	missense_variant	3/19	1	NM_153460.4	P4

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00188 AC: 353 AN: 187822 Hom.: 1 AF XY: 0.00201 AC XY: 202 AN XY: 100480

Gnomad AFR exome AF: 0.000709

Gnomad AMR exome AF: 0.000111

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000627

Gnomad FIN exome AF: 0.00187

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00277 AC: 3951 AN: 1424142 Hom.: 9 Cov.: 33 AF XY: 0.00272 AC XY: 1919 AN XY: 705348

Gnomad4 AFR exome AF: 0.000555

Gnomad4 AMR exome AF: 0.000235

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.000987

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00330

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00186 AC: 284 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00166 AC XY: 124 AN XY: 74490

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00267 Hom.: 2

Bravo AF: 0.00176

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00172 AC: 207

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2022

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

IL17RC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2022

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

Candidiasis, familial, 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.93	D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0058	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.0030	D;D;D;D;.;D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;D;.;D;D;.;D;.;.
Vest4		0.49
MVP		0.13
MPC		0.77
ClinPred		0.015	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.33

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

Other links and lift over

dbSNP: rs143412184; hg19: chr3-9959753;