Genetic Variant IL4R:p.Gln576Arg (chr16-27363079-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000418.4(IL4R):c.1727A>G(p.Gln576Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,613,910 control chromosomes in the GnomAD database, including 54,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.35 ( 12743 hom., cov: 33)

Exomes 𝑓: 0.22 ( 41529 hom. )

Consequence

IL4R
NM_000418.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.05

Publications

397 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1686489E-6).

BP6

Variant 16-27363079-A-G is Benign according to our data. Variant chr16-27363079-A-G is described in ClinVar as Benign. ClinVar VariationId is 14665.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4 link	c.1727A>G	p.Gln576Arg	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.1727A>G	p.Gln576Arg	missense_variant	Exon 11 of 11	1	NM_000418.4	ENSP00000379111.2

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52747

AN:

152070

Hom.:

12686

Cov.:

show subpopulations

Gnomad AFR

AF:

0.688

Gnomad AMI

AF:

0.0912

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.155

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.195

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.306

GnomAD2 exomes

AF:

0.248

AC:

61954

AN:

250126

AF XY:

0.235

show subpopulations

Gnomad AFR exome

AF:

0.703

Gnomad AMR exome

AF:

0.300

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.199

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.225

AC:

328389

AN:

1461722

Hom.:

41529

Cov.:

AF XY:

0.222

AC XY:

161640

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.707

AC:

23671

AN:

33480

American (AMR)

AF:

0.301

AC:

13465

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

4415

AN:

26136

East Asian (EAS)

AF:

0.159

AC:

6310

AN:

39698

South Asian (SAS)

AF:

0.224

AC:

19307

AN:

86252

European-Finnish (FIN)

AF:

0.200

AC:

10682

AN:

53292

Middle Eastern (MID)

AF:

0.192

AC:

1109

AN:

5768

European-Non Finnish (NFE)

AF:

0.211

AC:

234911

AN:

1111990

Other (OTH)

AF:

0.240

AC:

14519

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

16761

33522

50284

67045

83806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8434

16868

25302

33736

42170

<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:

0.347

AC:

52863

AN:

152188

Hom.:

12743

Cov.:

AF XY:

0.343

AC XY:

25484

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.688

AC:

28569

AN:

41502

American (AMR)

AF:

0.317

AC:

4851

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.171

AC:

593

AN:

3468

East Asian (EAS)

AF:

0.155

AC:

802

AN:

5168

South Asian (SAS)

AF:

0.226

AC:

1092

AN:

4826

European-Finnish (FIN)

AF:

0.195

AC:

2066

AN:

10602

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.207

AC:

14101

AN:

68018

Other (OTH)

AF:

0.305

AC:

646

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1458

2917

4375

5834

7292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<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:

0.252

Hom.:

22216

Bravo

AF:

0.369

TwinsUK

AF:

0.211

AC:

781

ALSPAC

AF:

0.215

AC:

829

ESP6500AA

AF:

0.674

AC:

2963

ESP6500EA

AF:

0.204

AC:

1753

ExAC

AF:

0.254

AC:

30865

Asia WGS

AF:

0.278

AC:

967

AN:

3478

EpiCase

AF:

0.195

EpiControl

AF:

0.189

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

RECLASSIFIED - MYOC POLYMORPHISM

Benign:1

Feb 01, 2005

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.074

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.0

.;T;T

MetaRNN

Benign

0.0000012

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.5

N;N;.

PhyloP100

1.0

PrimateAI

Benign

0.38

PROVEAN

Benign

0.89

N;N;.

REVEL

Benign

0.065

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;T

Vest4

0.031

ClinPred

0.00026

GERP RS

2.8

Varity_R

0.018

gMVP

0.14

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over