16-27344882-A-G

Variant names:

Variant summary

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

The NM_000418.4(IL4R):c.223A>G(p.Ile75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,613,710 control chromosomes in the GnomAD database, including 166,267 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.46 ( 15980 hom., cov: 33)

Exomes 𝑓: 0.45 ( 150287 hom. )

Consequence

IL4R
NM_000418.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: -0.221

Publications

281 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=2.4071336E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000418.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL4R	NM_000418.4	MANE Select	c.223A>G	p.Ile75Val	missense	Exon 5 of 11	NP_000409.1
IL4R	NM_001257406.2		c.223A>G	p.Ile75Val	missense	Exon 4 of 10	NP_001244335.1
IL4R	NM_001257407.2		c.178A>G	p.Ile60Val	missense	Exon 5 of 11	NP_001244336.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL4R	ENST00000395762.7	TSL:1 MANE Select	c.223A>G	p.Ile75Val	missense	Exon 5 of 11	ENSP00000379111.2
IL4R	ENST00000543915.6	TSL:1	c.223A>G	p.Ile75Val	missense	Exon 4 of 10	ENSP00000441667.2
IL4R	ENST00000170630.6	TSL:5	c.178A>G	p.Ile60Val	missense	Exon 3 of 9	ENSP00000170630.3

Frequencies

GnomAD3 genomes

AF:

0.456

AC:

69336

AN:

152006

Hom.:

15955

Cov.:

show subpopulations

Gnomad AFR

AF:

0.496

Gnomad AMI

AF:

0.507

Gnomad AMR

AF:

0.433

Gnomad ASJ

AF:

0.396

Gnomad EAS

AF:

0.525

Gnomad SAS

AF:

0.438

Gnomad FIN

AF:

0.364

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.450

Gnomad OTH

AF:

0.466

GnomAD2 exomes

AF:

0.448

AC:

112362

AN:

250934

AF XY:

0.447

show subpopulations

Gnomad AFR exome

AF:

0.497

Gnomad AMR exome

AF:

0.454

Gnomad ASJ exome

AF:

0.401

Gnomad EAS exome

AF:

0.509

Gnomad FIN exome

AF:

0.364

Gnomad NFE exome

AF:

0.451

Gnomad OTH exome

AF:

0.452

GnomAD4 exome

AF:

0.452

AC:

660298

AN:

1461586

Hom.:

150287

Cov.:

AF XY:

0.452

AC XY:

328928

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.496

AC:

16599

AN:

33478

American (AMR)

AF:

0.450

AC:

20131

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

10467

AN:

26136

East Asian (EAS)

AF:

0.564

AC:

22388

AN:

39700

South Asian (SAS)

AF:

0.439

AC:

37866

AN:

86254

European-Finnish (FIN)

AF:

0.369

AC:

19703

AN:

53384

Middle Eastern (MID)

AF:

0.458

AC:

2627

AN:

5738

European-Non Finnish (NFE)

AF:

0.452

AC:

503027

AN:

1111796

Other (OTH)

AF:

0.455

AC:

27490

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

19098

38196

57293

76391

95489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15206

30412

45618

60824

76030

<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:

0.456

AC:

69416

AN:

152124

Hom.:

15980

Cov.:

AF XY:

0.451

AC XY:

33541

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.496

AC:

20575

AN:

41496

American (AMR)

AF:

0.434

AC:

6631

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

1375

AN:

3470

East Asian (EAS)

AF:

0.524

AC:

2710

AN:

5174

South Asian (SAS)

AF:

0.439

AC:

2117

AN:

4822

European-Finnish (FIN)

AF:

0.364

AC:

3857

AN:

10584

Middle Eastern (MID)

AF:

0.449

AC:

132

AN:

294

European-Non Finnish (NFE)

AF:

0.450

AC:

30570

AN:

67972

Other (OTH)

AF:

0.468

AC:

989

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

2003

4006

6010

8013

10016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.447

Hom.:

46826

Bravo

AF:

0.465

TwinsUK

AF:

0.451

AC:

1671

ALSPAC

AF:

0.452

AC:

1741

ESP6500AA

AF:

0.498

AC:

2189

ESP6500EA

AF:

0.448

AC:

3853

ExAC

AF:

0.451

AC:

54701

Asia WGS

AF:

0.460

AC:

1600

AN:

3478

EpiCase

AF:

0.456

EpiControl

AF:

0.453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

IL4R-related disorder

Uncertain:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

RECLASSIFIED - MYOC POLYMORPHISM

Benign:1

Oct 01, 2005

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.14

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.036

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.28

MetaRNN

Benign

0.00024

MetaSVM

Benign

-0.94

PhyloP100

-0.22

PrimateAI

Benign

0.33

PROVEAN

Benign

0.34

REVEL

Benign

0.027

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.015

MPC

0.10

ClinPred

0.0030

GERP RS

0.17

PromoterAI

0.00030

Neutral

(source)

Varity_R

0.065

gMVP

0.21

Mutation Taster

=91/9

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over