NM_002186.3:c.991G>A

Variant names:

• chrX-156009834-G-A
• rs142104921
• NM_002186.3:c.991G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002186.3(IL9R):​c.991G>A​(p.Gly331Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,283,524 control chromosomes in the GnomAD database, including 2,010 homozygotes. There are 8,866 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.032 (555 hom., 1345 hem., cov: 18)
  • Exomes 𝑓: 0.012 (1455 hom. 7521 hem.)
• Consequence: IL9R NM_002186.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.349

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]

ENSG00000270726 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020613968).
• BP6: Variant X-156009834-G-A is Benign according to our data. Variant chrX-156009834-G-A is described in ClinVar as [Benign]. Clinvar id is 769193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL9R	NM_002186.3	c.991G>A	p.Gly331Arg	missense_variant	Exon 9 of 9	ENST00000244174.11	NP_002177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL9R	ENST00000244174.11	c.991G>A	p.Gly331Arg	missense_variant	Exon 9 of 9	1	NM_002186.3	ENSP00000244174.5
IL9R	ENST00000369423.7	c.1011G>A	p.Thr337Thr	synonymous_variant	Exon 9 of 9	1		ENSP00000358431.2
ENSG00000270726	ENST00000483543.7	n.433+2227G>A		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 2896 AN: 89966 Hom.: 550 Cov.: 18 AF XY: 0.0311 AC XY: 1329 AN XY: 42722

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00601

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.00858

Gnomad EAS AF: 0.0163

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00870

Gnomad NFE AF: 0.00928

Gnomad OTH AF: 0.0233

GnomAD3 exomes AF: 0.00702 AC: 1479 AN: 210536 Hom.: 160 AF XY: 0.00561 AC XY: 639 AN XY: 113906

Gnomad AFR exome AF: 0.0725

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.00215

Gnomad EAS exome AF: 0.00878

Gnomad SAS exome AF: 0.00308

Gnomad FIN exome AF: 0.00417

Gnomad NFE exome AF: 0.000840

Gnomad OTH exome AF: 0.00578

GnomAD4 exome AF: 0.0118 AC: 14040 AN: 1193490 Hom.: 1455 Cov.: 30 AF XY: 0.0128 AC XY: 7521 AN XY: 585888

Gnomad4 AFR exome AF: 0.0646

Gnomad4 AMR exome AF: 0.0144

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.0483

Gnomad4 FIN exome AF: 0.0462

Gnomad4 NFE exome AF: 0.00427

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0324 AC: 2913 AN: 90034 Hom.: 555 Cov.: 18 AF XY: 0.0314 AC XY: 1345 AN XY: 42788

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.00858

Gnomad4 EAS AF: 0.0163

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.00928

Gnomad4 OTH AF: 0.0228

ESP6500AA AF: 0.0348 AC: 151

ESP6500EA AF: 0.000599 AC: 5

ExAC AF: 0.00602 AC: 707

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.25
DANN	Benign	0.61
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.00040	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.94	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.012
Sift	Benign	1.0	T
Sift4G	Benign	0.97	T
Polyphen		0.0	B
MutPred		0.19		Loss of sheet (P = 0.0011);
MVP		0.41
MPC		1.8
ClinPred		0.000052	T
GERP RS		0.25
Varity_R		0.052

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs142104921; hg19: chrX-155239499; COSMIC: COSV54899750; COSMIC: COSV54899750;