16-27345014-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_000418.4(IL4R):c.355G>A(p.Glu119Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,586,516 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

IL4R
NM_000418.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.16

Publications

2 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: Likely_benign. The variant received -2 ACMG points.

PM1

In a mutagenesis_site No effect on IL4 binding. (size 0) in uniprot entity IL4RA_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.02783522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4 link	c.355G>A	p.Glu119Lys	missense_variant	Exon 5 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.355G>A	p.Glu119Lys	missense_variant	Exon 5 of 11	1	NM_000418.4	ENSP00000379111.2		P24394-1

Frequencies

GnomAD3 genomes

AF:

0.000304

AC:

AN:

151454

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000960

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000590

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000300

AC:

AN:

250352

AF XY:

0.000295

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000599

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000410

AC:

588

AN:

1435062

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

288

AN XY:

713562

show subpopulations

African (AFR)

AF:

0.0000610

AC:

AN:

32802

American (AMR)

AF:

0.000182

AC:

AN:

43872

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25254

East Asian (EAS)

AF:

0.00

AC:

AN:

38070

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86008

European-Finnish (FIN)

AF:

0.0000598

AC:

AN:

50160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.000511

AC:

559

AN:

1094574

Other (OTH)

AF:

0.000238

AC:

AN:

58722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000304

AC:

AN:

151454

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

73958

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41352

American (AMR)

AF:

0.000197

AC:

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.0000960

AC:

AN:

10412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000590

AC:

AN:

67812

Other (OTH)

AF:

0.000480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000589

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.355G>A (p.E119K) alteration is located in exon 5 (coding exon 3) of the IL4R gene. This alteration results from a G to A substitution at nucleotide position 355, causing the glutamic acid (E) at amino acid position 119 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.43

CADD

Benign

3.4

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.072

.;T;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.74

.;.;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.028

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-1.2

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

N;N;N;N;.

REVEL

Benign

0.13

Sift

Benign

0.25

T;T;T;T;.

Sift4G

Benign

0.43

T;T;T;T;T

Polyphen

0.10

.;B;B;.;.

Vest4

0.11, 0.10, 0.095

MVP

0.39

MPC

0.15

ClinPred

0.026

GERP RS

-6.2

PromoterAI

0.032

Neutral

(source)

Varity_R

0.13

gMVP

0.44

Mutation Taster

=87/13

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

16-27345014-G-A

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