rs2234895

Variant names:

• chr16-27346606-C-T
• rs2234895
• NM_000418.4:c.501C>T
• IL4R p.Asn167Asn

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001257997.2(IL4R):​c.26C>T​(p.Thr9Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0799 in 1,613,662 control chromosomes in the GnomAD database, including 5,628 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T9T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.072 (481 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5147 hom.)
• Consequence: IL4R NM_001257997.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.721
• Publications: 23 publications found

Genes affected

IL4R (HGNC:6015): (interleukin 4 receptor) This gene encodes the alpha chain of the interleukin-4 receptor, a type I transmembrane protein that can bind interleukin 4 and interleukin 13 to regulate IgE production. The encoded protein also can bind interleukin 4 to promote differentiation of Th2 cells. A soluble form of the encoded protein can be produced by proteolysis of the membrane-bound protein, and this soluble form can inhibit IL4-mediated cell proliferation and IL5 upregulation by T-cells. Allelic variations in this gene have been associated with atopy, a condition that can manifest itself as allergic rhinitis, sinusitus, asthma, or eczema. Polymorphisms in this gene are also associated with resistance to human immunodeficiency virus type-1 infection. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

IL4R Gene-Disease associations (from GenCC):

• IgE responsiveness, atopic

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257997.2. 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
	IL4R	NM_000418.4	MANE Select	c.501C>T	p.Asn167Asn	synonymous	Exon 6 of 11	NP_000409.1	P24394-1
	IL4R	NM_001257997.2		c.26C>T	p.Thr9Met	missense	Exon 5 of 10	NP_001244926.1
	IL4R	NM_001257406.2		c.501C>T	p.Asn167Asn	synonymous	Exon 5 of 10	NP_001244335.1	P24394-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL4R	ENST00000395762.7	TSL:1 MANE Select	c.501C>T	p.Asn167Asn	synonymous	Exon 6 of 11	ENSP00000379111.2	P24394-1
	IL4R	ENST00000543915.6	TSL:1	c.501C>T	p.Asn167Asn	synonymous	Exon 5 of 10	ENSP00000441667.2	P24394-1
	IL4R	ENST00000912076.1		c.522C>T	p.Asn174Asn	synonymous	Exon 5 of 10	ENSP00000582135.1

Frequencies

GnomAD3 genomes AF: 0.0722 AC: 10979 AN: 152128 Hom.: 481 Cov.: 32

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0573

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0491

Gnomad FIN AF: 0.0794

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0891

Gnomad OTH AF: 0.0765

GnomAD2 exomes AF: 0.0687 AC: 17271 AN: 251266 AF XY: 0.0698

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.0379

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0766

Gnomad NFE exome AF: 0.0893

Gnomad OTH exome AF: 0.0840

GnomAD4 exome AF: 0.0807 AC: 117967 AN: 1461416 Hom.: 5147 Cov.: 32 AF XY: 0.0803 AC XY: 58376 AN XY: 727002

African (AFR) AF: 0.0549 AC: 1838 AN: 33474

American (AMR) AF: 0.0413 AC: 1845 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 3072 AN: 26132

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0525 AC: 4527 AN: 86252

European-Finnish (FIN) AF: 0.0750 AC: 3995 AN: 53296

Middle Eastern (MID) AF: 0.124 AC: 715 AN: 5768

European-Non Finnish (NFE) AF: 0.0875 AC: 97219 AN: 1111686

Other (OTH) AF: 0.0786 AC: 4744 AN: 60384

GnomAD4 genome AF: 0.0721 AC: 10980 AN: 152246 Hom.: 481 Cov.: 32 AF XY: 0.0703 AC XY: 5234 AN XY: 74444

African (AFR) AF: 0.0575 AC: 2389 AN: 41528

American (AMR) AF: 0.0572 AC: 875 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3468

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5192

South Asian (SAS) AF: 0.0491 AC: 237 AN: 4824

European-Finnish (FIN) AF: 0.0794 AC: 842 AN: 10610

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0891 AC: 6059 AN: 68012

Other (OTH) AF: 0.0757 AC: 160 AN: 2114

Alfa AF: 0.0829 Hom.: 984

Bravo AF: 0.0699

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0944

EpiControl AF: 0.0933

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.0
DANN	Benign	0.41
PhyloP100		-0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2234895;

hg19: chr16-27357927;

COSMIC: COSV107244637;