Genetic Variant IL4R:p.Ser436Leu (chr16-27362659-C-T) – 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.1307C>T(p.Ser436Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,614,050 control chromosomes in the GnomAD database, including 1,594 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.036 ( 125 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1469 hom. )

Consequence

IL4R
NM_000418.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.51

Publications

30 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=0.0020773709).

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4 link	c.1307C>T	p.Ser436Leu	missense_variant	Exon 11 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.1307C>T	p.Ser436Leu	missense_variant	Exon 11 of 11	1	NM_000418.4	ENSP00000379111.2		P24394-1

Frequencies

GnomAD3 genomes

AF:

0.0357

AC:

5430

AN:

152066

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0278

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0735

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0340

Gnomad FIN

AF:

0.0277

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0435

Gnomad OTH

AF:

0.0383

GnomAD2 exomes

AF:

0.0356

AC:

8935

AN:

250858

AF XY:

0.0370

show subpopulations

Gnomad AFR exome

AF:

0.0282

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0704

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.0278

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0465

GnomAD4 exome

AF:

0.0427

AC:

62491

AN:

1461866

Hom.:

1469

Cov.:

AF XY:

0.0430

AC XY:

31297

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0280

AC:

936

AN:

33480

American (AMR)

AF:

0.0207

AC:

926

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0730

AC:

1909

AN:

26136

East Asian (EAS)

AF:

0.000378

AC:

AN:

39700

South Asian (SAS)

AF:

0.0392

AC:

3381

AN:

86258

European-Finnish (FIN)

AF:

0.0301

AC:

1608

AN:

53408

Middle Eastern (MID)

AF:

0.0822

AC:

474

AN:

5768

European-Non Finnish (NFE)

AF:

0.0454

AC:

50513

AN:

1111998

Other (OTH)

AF:

0.0452

AC:

2729

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

3808

7616

11424

15232

19040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1900

3800

5700

7600

9500

<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:

0.0357

AC:

5433

AN:

152184

Hom.:

125

Cov.:

AF XY:

0.0342

AC XY:

2547

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0279

AC:

1158

AN:

41506

American (AMR)

AF:

0.0325

AC:

497

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0735

AC:

255

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0340

AC:

164

AN:

4818

European-Finnish (FIN)

AF:

0.0277

AC:

294

AN:

10608

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0435

AC:

2956

AN:

67986

Other (OTH)

AF:

0.0379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

263

527

790

1054

1317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0420

Hom.:

240

Bravo

AF:

0.0348

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0462

AC:

178

ESP6500AA

AF:

0.0241

AC:

106

ESP6500EA

AF:

0.0449

AC:

386

ExAC

AF:

0.0360

AC:

4366

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0460

EpiControl

AF:

0.0432

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.29

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.10

T;T;.

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.69

.;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.23

N;N;.

PhyloP100

-1.5

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.78

N;N;.

REVEL

Benign

0.068

Sift

Benign

0.46

T;T;.

Sift4G

Benign

0.23

T;T;T

Polyphen

0.014

B;B;.

Vest4

0.029

MPC

0.11

ClinPred

0.00030

GERP RS

-6.2

Varity_R

0.046

gMVP

0.072

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