16-27344903-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000418.4(IL4R):c.244G>A(p.Ala82Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,614,220 control chromosomes in the GnomAD database, including 321 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 Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A82V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0091 ( 46 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 275 hom. )

Consequence

IL4R
NM_000418.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -2.73

Publications

11 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=0.0023322105).

BP6

Variant 16-27344903-G-A is Benign according to our data. Variant chr16-27344903-G-A is described in ClinVar as [Benign]. Clinvar id is 3043783.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0091 (1387/152368) while in subpopulation EAS AF = 0.0433 (225/5192). AF 95% confidence interval is 0.0387. There are 46 homozygotes in GnomAd4. There are 937 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 46 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4 link	c.244G>A	p.Ala82Thr	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.244G>A	p.Ala82Thr	missense_variant	Exon 5 of 11	1	NM_000418.4	ENSP00000379111.2		P24394-1

Frequencies

GnomAD3 genomes

AF:

0.00911

AC:

1387

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0432

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0850

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.0127

AC:

3191

AN:

251248

AF XY:

0.0119

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00700

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0371

Gnomad FIN exome

AF:

0.0863

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00555

AC:

8107

AN:

1461852

Hom.:

275

Cov.:

AF XY:

0.00541

AC XY:

3934

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.00631

AC:

282

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00138

AC:

AN:

26136

East Asian (EAS)

AF:

0.0506

AC:

2007

AN:

39700

South Asian (SAS)

AF:

0.00121

AC:

104

AN:

86258

European-Finnish (FIN)

AF:

0.0836

AC:

4463

AN:

53388

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000796

AC:

885

AN:

1112006

Other (OTH)

AF:

0.00528

AC:

319

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

426

852

1278

1704

2130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00910

AC:

1387

AN:

152368

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

937

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41592

American (AMR)

AF:

0.00327

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.0433

AC:

225

AN:

5192

South Asian (SAS)

AF:

0.00248

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0850

AC:

903

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00228

AC:

155

AN:

68032

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

138

208

277

346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00332

Hom.:

Bravo

AF:

0.00299

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0111

AC:

1342

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

IL4R-related disorder

Benign:1

Aug 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0020

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.030

.;T;T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.56

.;.;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-2.7

PrimateAI

Benign

0.25

PROVEAN

Benign

0.020

N;N;N;N;.

REVEL

Benign

0.014

Sift

Benign

0.81

T;T;T;T;.

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

0.13

.;B;B;.;.

Vest4

0.027, 0.030, 0.018

MPC

0.12

ClinPred

0.00097

GERP RS

-5.4

PromoterAI

0.036

Neutral

(source)

Varity_R

0.055

gMVP

0.28

Mutation Taster

=97/3

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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16-27344903-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