dbSNP rs1805016: IL4R:p.Ser752Ala (chr16-27363606-T-G) – 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.2254T>G(p.Ser752Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0647 in 1,613,744 control chromosomes in the GnomAD database, including 6,244 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 0.12 ( 2257 hom., cov: 32)

Exomes 𝑓: 0.059 ( 3987 hom. )

Consequence

IL4R
NM_000418.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.786

Publications

44 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=0.003445685).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4 link	c.2254T>G	p.Ser752Ala	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.2254T>G	p.Ser752Ala	missense_variant	Exon 11 of 11	1	NM_000418.4	ENSP00000379111.2		P24394-1

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18643

AN:

151956

Hom.:

2246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0708

Gnomad ASJ

AF:

0.0899

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0382

Gnomad FIN

AF:

0.0294

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0528

Gnomad OTH

AF:

0.107

GnomAD2 exomes

AF:

0.0637

AC:

15957

AN:

250646

AF XY:

0.0591

show subpopulations

Gnomad AFR exome

AF:

0.320

Gnomad AMR exome

AF:

0.0401

Gnomad ASJ exome

AF:

0.0864

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0292

Gnomad NFE exome

AF:

0.0549

Gnomad OTH exome

AF:

0.0687

GnomAD4 exome

AF:

0.0587

AC:

85792

AN:

1461672

Hom.:

3987

Cov.:

AF XY:

0.0579

AC XY:

42102

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.325

AC:

10884

AN:

33476

American (AMR)

AF:

0.0446

AC:

1993

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0895

AC:

2339

AN:

26136

East Asian (EAS)

AF:

0.000353

AC:

AN:

39700

South Asian (SAS)

AF:

0.0422

AC:

3642

AN:

86258

European-Finnish (FIN)

AF:

0.0318

AC:

1694

AN:

53266

Middle Eastern (MID)

AF:

0.121

AC:

700

AN:

5766

European-Non Finnish (NFE)

AF:

0.0541

AC:

60130

AN:

1111962

Other (OTH)

AF:

0.0728

AC:

4396

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

4759

9518

14277

19036

23795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2390

4780

7170

9560

11950

<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:

0.123

AC:

18690

AN:

152072

Hom.:

2257

Cov.:

AF XY:

0.118

AC XY:

8764

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.312

AC:

12935

AN:

41466

American (AMR)

AF:

0.0706

AC:

1079

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0899

AC:

312

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0382

AC:

184

AN:

4816

European-Finnish (FIN)

AF:

0.0294

AC:

311

AN:

10590

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0528

AC:

3589

AN:

67964

Other (OTH)

AF:

0.106

AC:

224

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

727

1455

2182

2910

3637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.0784

Hom.:

2184

Bravo

AF:

0.133

TwinsUK

AF:

0.0523

AC:

194

ALSPAC

AF:

0.0568

AC:

219

ESP6500AA

AF:

0.305

AC:

1342

ESP6500EA

AF:

0.0538

AC:

463

ExAC

AF:

0.0687

AC:

8342

Asia WGS

AF:

0.0390

AC:

136

AN:

3478

EpiCase

AF:

0.0581

EpiControl

AF:

0.0558

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.90

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.15

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.42

.;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

-0.79

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.84

N;N;.

REVEL

Benign

0.040

Sift

Benign

0.12

T;T;.

Sift4G

Benign

0.094

T;T;T

Polyphen

0.18

B;B;.

Vest4

0.066

MPC

0.12

ClinPred

0.0012

GERP RS

-4.4

Varity_R

0.049

gMVP

0.058

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