NM_014339.7:c.1819G>A

Variant names:

• chr22-17109038-G-A
• rs28376631
• NM_014339.7:c.1819G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014339.7(IL17RA):​c.1819G>A​(p.Glu607Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,593,494 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E607G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 34)
  • Exomes 𝑓: 0.00083 (17 hom.)
• Consequence: IL17RA NM_014339.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.35
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• chronic mucocutaneous candidiasis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003880918).
• BP6: Variant 22-17109038-G-A is Benign according to our data. Variant chr22-17109038-G-A is described in ClinVar as Benign. ClinVar VariationId is 542922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00789 (1202/152352) while in subpopulation AFR AF = 0.0271 (1125/41588). AF 95% confidence interval is 0.0257. There are 17 homozygotes in GnomAd4. There are 582 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.1819G>A	p.Glu607Lys	missense	Exon 13 of 13	NP_055154.3
	IL17RA	NM_001289905.2		c.1717G>A	p.Glu573Lys	missense	Exon 12 of 12	NP_001276834.1	Q96F46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL17RA	ENST00000319363.11	TSL:1 MANE Select	c.1819G>A	p.Glu607Lys	missense	Exon 13 of 13	ENSP00000320936.6	Q96F46-1
	IL17RA	ENST00000940705.1		c.1807G>A	p.Glu603Lys	missense	Exon 12 of 12	ENSP00000610764.1
	IL17RA	ENST00000612619.2	TSL:5	c.1717G>A	p.Glu573Lys	missense	Exon 12 of 12	ENSP00000479970.1	Q96F46-2

Frequencies

GnomAD3 genomes AF: 0.00783 AC: 1192 AN: 152234 Hom.: 17 Cov.: 34

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00195 AC: 422 AN: 216528 AF XY: 0.00150

Gnomad AFR exome AF: 0.0270

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000903

GnomAD4 exome AF: 0.000834 AC: 1202 AN: 1441142 Hom.: 17 Cov.: 44 AF XY: 0.000735 AC XY: 527 AN XY: 716908

African (AFR) AF: 0.0273 AC: 911 AN: 33402

American (AMR) AF: 0.00151 AC: 66 AN: 43792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.0000822 AC: 7 AN: 85172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38434

Middle Eastern (MID) AF: 0.00319 AC: 18 AN: 5650

European-Non Finnish (NFE) AF: 0.0000847 AC: 94 AN: 1109354

Other (OTH) AF: 0.00177 AC: 106 AN: 59972

GnomAD4 genome AF: 0.00789 AC: 1202 AN: 152352 Hom.: 17 Cov.: 34 AF XY: 0.00781 AC XY: 582 AN XY: 74504

African (AFR) AF: 0.0271 AC: 1125 AN: 41588

American (AMR) AF: 0.00333 AC: 51 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68028

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00335 Hom.: 7

Bravo AF: 0.00909

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0213 AC: 93

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.00228 AC: 275

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency 51 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.099
Sift	Benign	0.11	T
Sift4G	Benign	0.084	T
Polyphen		0.79	P
Vest4		0.078
MVP		0.30
MPC		0.24
ClinPred		0.033	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.52
Mutation Taster		=91/9	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: rs28376631; hg19: chr22-17589928;