rs140221307

Variant names:

• chr22-17105867-T-C
• rs140221307
• NM_014339.7:c.958T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_014339.7(IL17RA):​c.958T>C​(p.Trp320Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00389 in 1,613,944 control chromosomes in the GnomAD database, including 19 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. W320C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (19 hom.)
• Consequence: IL17RA NM_014339.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 4.70
• Publications: 19 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• chronic mucocutaneous candidiasis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0836069).
• BP6: Variant 22-17105867-T-C is Benign according to our data. Variant chr22-17105867-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 340587.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00233 (355/152318) while in subpopulation NFE AF = 0.00457 (311/68026). AF 95% confidence interval is 0.00415. There are 0 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AD,AR gene

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.958T>C	p.Trp320Arg	missense	Exon 11 of 13	NP_055154.3
	IL17RA	NM_001289905.2		c.943+265T>C		intron	N/A	NP_001276834.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL17RA	ENST00000319363.11	TSL:1 MANE Select	c.958T>C	p.Trp320Arg	missense	Exon 11 of 13	ENSP00000320936.6
	IL17RA	ENST00000940705.1		c.946T>C	p.Trp316Arg	missense	Exon 10 of 12	ENSP00000610764.1
	IL17RA	ENST00000962147.1		c.619T>C	p.Trp207Arg	missense	Exon 8 of 10	ENSP00000632206.1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00173 AC: 435 AN: 251206 AF XY: 0.00170

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00405 AC: 5917 AN: 1461626 Hom.: 19 Cov.: 33 AF XY: 0.00386 AC XY: 2806 AN XY: 727132

African (AFR) AF: 0.000358 AC: 12 AN: 33474

American (AMR) AF: 0.00105 AC: 47 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00496 AC: 5510 AN: 1111840

Other (OTH) AF: 0.00551 AC: 333 AN: 60384

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00223 AC XY: 166 AN XY: 74480

African (AFR) AF: 0.000698 AC: 29 AN: 41566

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00457 AC: 311 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00329 Hom.: 7

Bravo AF: 0.00259

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00180 AC: 219

EpiCase AF: 0.00480

EpiControl AF: 0.00332

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Immunodeficiency 51 (2)
-	1	1	not provided (2)
-	1	-	Familial Candidiasis, Recessive (1)
-	1	-	IL17RA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.46		Loss of helix (P = 0.0558)
MVP		0.27
MPC		1.0
ClinPred		0.063	T
GERP RS		5.2
Varity_R		0.55
gMVP		0.67
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs140221307; hg19: chr22-17586757; COSMIC: COSV100083554;