rs6522

chrX-156005413-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002186.3(IL9R):c.715G>C(p.Glu239Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,204 control chromosomes in the GnomAD database, including 25 homozygotes. There are 742 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0061 (10 hom., 368 hem., cov: 32)
  • Exomes 𝑓: 0.00070 (15 hom. 374 hem.)
• Consequence: IL9R NM_002186.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0230

Genes affected

IL9R (HGNC:6030): (interleukin 9 receptor) The protein encoded by this gene is a cytokine receptor that specifically mediates the biological effects of interleukin 9 (IL9). The functional IL9 receptor complex requires this protein as well as the interleukin 2 receptor, gamma (IL2RG), a common gamma subunit shared by the receptors of many different cytokines. The ligand binding of this receptor leads to the activation of various JAK kinases and STAT proteins, which connect to different biologic responses. This gene is located at the pseudoautosomal regions of X and Y chromosomes. Genetic studies suggested an association of this gene with the development of asthma. Multiple pseudogenes on chromosome 9, 10, 16, and 18 have been described. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034928322).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0061 (929/152214) while in subpopulation AFR AF= 0.0215 (893/41534). AF 95% confidence interval is 0.0203. There are 10 homozygotes in gnomad4. There are 368 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL9R	NM_002186.3	c.715G>C	p.Glu239Gln	missense_variant	6/9	ENST00000244174.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL9R	ENST00000244174.11	c.715G>C	p.Glu239Gln	missense_variant	6/9	1	NM_002186.3	P1
IL9R	ENST00000369423.7	c.820G>C	p.Glu274Gln	missense_variant	7/9	1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 925 AN: 152096 Hom.: 10 Cov.: 32 AF XY: 0.00493 AC XY: 366 AN XY: 74286

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.0000588

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.00160 AC: 403 AN: 251142 Hom.: 3 AF XY: 0.00101 AC XY: 137 AN XY: 135728

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000699 AC: 1021 AN: 1460990 Hom.: 15 Cov.: 33 AF XY: 0.000515 AC XY: 374 AN XY: 726806

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00610 AC: 929 AN: 152214 Hom.: 10 Cov.: 32 AF XY: 0.00495 AC XY: 368 AN XY: 74414

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00475

Bravo AF: 0.00666

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00193 AC: 234

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	9.2
Dann	Benign	0.97
DEOGEN2	Benign	0.045	T;.
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.019
Sift	Benign	0.13	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.11	B;.
MVP		0.27
MPC		0.0025
ClinPred		0.0026	T
GERP RS		0.32
Varity_R		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6522; hg19: chrX-155235078; COSMIC: COSV99054967; COSMIC: COSV99054967;