Genetic Variant IL4R:p.Ser503Pro (chr16-27362859-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000418.4(IL4R):c.1507T>C(p.Ser503Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,858 control chromosomes in the GnomAD database, including 25,776 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 not provided (no stars).

Frequency

Genomes: 𝑓 0.22 ( 4428 hom., cov: 32)

Exomes 𝑓: 0.17 ( 21348 hom. )

Consequence

IL4R
NM_000418.4 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.124

Publications

157 publications found

Variant links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.003134787).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4 link	c.1507T>C	p.Ser503Pro	missense_variant	Exon 11 of 11	ENST00000395762.7	NP_000409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL4R	ENST00000395762.7 link	c.1507T>C	p.Ser503Pro	missense_variant	Exon 11 of 11	1	NM_000418.4	ENSP00000379111.2

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

33005

AN:

151926

Hom.:

4411

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.201

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.0723

Gnomad SAS

AF:

0.0990

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.163

Gnomad OTH

AF:

0.205

GnomAD2 exomes

AF:

0.159

AC:

39895

AN:

251224

AF XY:

0.152

show subpopulations

Gnomad AFR exome

AF:

0.385

Gnomad AMR exome

AF:

0.161

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.0796

Gnomad FIN exome

AF:

0.133

Gnomad NFE exome

AF:

0.163

Gnomad OTH exome

AF:

0.156

GnomAD4 exome

AF:

0.165

AC:

241533

AN:

1461814

Hom.:

21348

Cov.:

AF XY:

0.162

AC XY:

117745

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.383

AC:

12821

AN:

33480

American (AMR)

AF:

0.163

AC:

7298

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

3530

AN:

26136

East Asian (EAS)

AF:

0.0715

AC:

2837

AN:

39700

South Asian (SAS)

AF:

0.101

AC:

8676

AN:

86258

European-Finnish (FIN)

AF:

0.138

AC:

7348

AN:

53350

Middle Eastern (MID)

AF:

0.143

AC:

826

AN:

5768

European-Non Finnish (NFE)

AF:

0.169

AC:

187900

AN:

1112002

Other (OTH)

AF:

0.170

AC:

10297

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

13969

27938

41907

55876

69845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6772

13544

20316

27088

33860

<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:

0.217

AC:

33065

AN:

152044

Hom.:

4428

Cov.:

AF XY:

0.211

AC XY:

15666

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.380

AC:

15759

AN:

41462

American (AMR)

AF:

0.201

AC:

3066

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

468

AN:

3464

East Asian (EAS)

AF:

0.0723

AC:

373

AN:

5162

South Asian (SAS)

AF:

0.0985

AC:

474

AN:

4814

European-Finnish (FIN)

AF:

0.125

AC:

1319

AN:

10592

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.163

AC:

11103

AN:

67956

Other (OTH)

AF:

0.204

AC:

430

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1273

2547

3820

5094

6367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.177

Hom.:

11962

Bravo

AF:

0.227

TwinsUK

AF:

0.170

AC:

630

ALSPAC

AF:

0.173

AC:

668

ESP6500AA

AF:

0.363

AC:

1595

ESP6500EA

AF:

0.162

AC:

1391

ExAC

AF:

0.163

AC:

19843

Asia WGS

AF:

0.131

AC:

456

AN:

3478

EpiCase

AF:

0.155

EpiControl

AF:

0.152

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

RECLASSIFIED - MYOC POLYMORPHISM

Other:1

Mar 07, 2025

OMIM

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

T;T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.44

.;T;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

L;L;.

PhyloP100

0.12

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.24

N;N;.

REVEL

Benign

0.085

Sift

Benign

0.27

T;T;.

Sift4G

Benign

0.12

T;T;T

Polyphen

0.54

P;P;.

Vest4

0.14

MPC

0.38

ClinPred

0.012

GERP RS

1.6

Varity_R

0.095

gMVP

0.20

Mutation Taster

=99/1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over