Genetic Variant IL4R:p.Asn167Asn (chr16-27346606-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000418.4(IL4R):c.501C>T(p.Asn167Asn) variant causes a synonymous 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.072 ( 481 hom., cov: 32)

Exomes 𝑓: 0.081 ( 5147 hom. )

Consequence

IL4R
NM_000418.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.721

Publications

23 publications found

Variant links:

COSMIC-nc: COSV107244637

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)

IL4R links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP7

Synonymous conserved (PhyloP=-0.721 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4 link	c.501C>T	p.Asn167Asn	synonymous_variant	Exon 6 of 11	ENST00000395762.7	NP_000409.1	P24394-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL4R	ENST00000395762.7 link	c.501C>T	p.Asn167Asn	synonymous_variant	Exon 6 of 11	1	NM_000418.4	ENSP00000379111.2		P24394-1

Frequencies

GnomAD3 genomes

AF:

0.0722

AC:

10979

AN:

152128

Hom.:

481

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0803

AC XY:

58376

AN XY:

727002

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

4953

9905

14858

19810

24763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3496

6992

10488

13984

17480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0721

AC:

10980

AN:

152246

Hom.:

481

Cov.:

AF XY:

0.0703

AC XY:

5234

AN XY:

74444

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0891

AC:

6059

AN:

68012

Other (OTH)

AF:

0.0757

AC:

160

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

542

1084

1627

2169

2711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0829

Hom.:

984

Bravo

AF:

0.0699

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0944

EpiControl

AF:

0.0933

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

3.0

(source)

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over