Genetic Variant IL4R:p.Ser436Leu (chr16-27362659-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000418.4(IL4R):c.1307C>T(p.Ser436Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,614,050 control chromosomes in the GnomAD database, including 1,594 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.036 ( 125 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1469 hom. )

Consequence

IL4R
NM_000418.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.51

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020773709).

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4 link	c.1307C>T	p.Ser436Leu	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.1307C>T	p.Ser436Leu	missense_variant	Exon 11 of 11	1	NM_000418.4	ENSP00000379111.2		P24394-1

Frequencies

GnomAD3 genomes

AF:

0.0357

AC:

5430

AN:

152066

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0278

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0735

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0340

Gnomad FIN

AF:

0.0277

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0435

Gnomad OTH

AF:

0.0383

GnomAD3 exomes

AF:

0.0356

AC:

8935

AN:

250858

Hom.:

207

AF XY:

0.0370

AC XY:

5015

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.0282

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0704

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0382

Gnomad FIN exome

AF:

0.0278

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0465

GnomAD4 exome

AF:

0.0427

AC:

62491

AN:

1461866

Hom.:

1469

Cov.:

AF XY:

0.0430

AC XY:

31297

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0280

Gnomad4 AMR exome

AF:

0.0207

Gnomad4 ASJ exome

AF:

0.0730

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.0392

Gnomad4 FIN exome

AF:

0.0301

Gnomad4 NFE exome

AF:

0.0454

Gnomad4 OTH exome

AF:

0.0452

GnomAD4 genome

AF:

0.0357

AC:

5433

AN:

152184

Hom.:

125

Cov.:

AF XY:

0.0342

AC XY:

2547

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0279

Gnomad4 AMR

AF:

0.0325

Gnomad4 ASJ

AF:

0.0735

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0340

Gnomad4 FIN

AF:

0.0277

Gnomad4 NFE

AF:

0.0435

Gnomad4 OTH

AF:

0.0379

Alfa

AF:

0.0428

Hom.:

198

Bravo

AF:

0.0348

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0462

AC:

178

ESP6500AA

AF:

0.0241

AC:

106

ESP6500EA

AF:

0.0449

AC:

386

ExAC

AF:

0.0360

AC:

4366

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0460

EpiControl

AF:

0.0432

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.29

DANN

Benign

0.38

DEOGEN2

Benign

0.10

T;T;.

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.69

.;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.23

N;N;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.78

N;N;.

REVEL

Benign

0.068

Sift

Benign

0.46

T;T;.

Sift4G

Benign

0.23

T;T;T

Polyphen

0.014

B;B;.

Vest4

0.029

MPC

0.11

ClinPred

0.00030

GERP RS

-6.2

Varity_R

0.046

gMVP

0.072

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over