chr22-17108393-G-T

Position:

• chr22-17108393-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014339.7(IL17RA):​c.1174G>T​(p.Val392Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00185 in 1,614,028 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: IL17RA NM_014339.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.35

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011312544).
• BP6: Variant 22-17108393-G-T is Benign according to our data. Variant chr22-17108393-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542925.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00149 (227/152316) while in subpopulation NFE AF= 0.00225 (153/68016). AF 95% confidence interval is 0.00196. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL17RA	NM_014339.7	c.1174G>T	p.Val392Leu	missense_variant	13/13	ENST00000319363.11	NP_055154.3
IL17RA	NM_001289905.2	c.1072G>T	p.Val358Leu	missense_variant	12/12		NP_001276834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL17RA	ENST00000319363.11	c.1174G>T	p.Val392Leu	missense_variant	13/13	1	NM_014339.7	ENSP00000320936.6
IL17RA	ENST00000612619.2	c.1072G>T	p.Val358Leu	missense_variant	12/12	5		ENSP00000479970.1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00162 AC: 407 AN: 251146 Hom.: 0 AF XY: 0.00147 AC XY: 200 AN XY: 135796

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00188 AC: 2754 AN: 1461712 Hom.: 3 Cov.: 54 AF XY: 0.00183 AC XY: 1331 AN XY: 727134

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00326

Gnomad4 NFE exome AF: 0.00214

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152316 Hom.: 0 Cov.: 34 AF XY: 0.00148 AC XY: 110 AN XY: 74484

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00123

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00180 AC: 219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Immunodeficiency 51 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 25, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

IL17RA-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 28, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.13
Sift	Benign	0.074	T;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.97	D;.
Vest4		0.31
MutPred		0.49		Loss of methylation at K397 (P = 0.0744);.;
MVP		0.16
MPC		0.70
ClinPred		0.30	T
GERP RS		4.8
Varity_R		0.32
gMVP		0.48

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: rs146478431; hg19: chr22-17589283; COSMIC: COSV60057133;