Genetic Variant NM_000418.4:c.1299T>C (chr16-27362651-T-C) – 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.1299T>C(p.Leu433Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,492 control chromosomes in the GnomAD database, including 24,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.25 ( 7921 hom., cov: 31)

Exomes 𝑓: 0.13 ( 16829 hom. )

Consequence

IL4R
NM_000418.4 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.16

Publications

21 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 (BayesDel_noAF=-0.91).

BP6

Variant 16-27362651-T-C is Benign according to our data. Variant chr16-27362651-T-C is described in ClinVar as Benign. ClinVar VariationId is 3056761.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4 link	c.1299T>C	p.Leu433Leu	synonymous_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.1299T>C	p.Leu433Leu	synonymous_variant	Exon 11 of 11	1	NM_000418.4	ENSP00000379111.2		P24394-1

Frequencies

GnomAD3 genomes

AF:

0.247

AC:

37440

AN:

151748

Hom.:

7880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.578

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.0674

Gnomad EAS

AF:

0.0714

Gnomad SAS

AF:

0.0645

Gnomad FIN

AF:

0.0965

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.214

GnomAD2 exomes

AF:

0.142

AC:

35650

AN:

250978

AF XY:

0.129

show subpopulations

Gnomad AFR exome

AF:

0.594

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.0685

Gnomad EAS exome

AF:

0.0792

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.131

AC:

190891

AN:

1461626

Hom.:

16829

Cov.:

AF XY:

0.126

AC XY:

91679

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.599

AC:

20035

AN:

33472

American (AMR)

AF:

0.160

AC:

7140

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0689

AC:

1800

AN:

26136

East Asian (EAS)

AF:

0.0711

AC:

2821

AN:

39700

South Asian (SAS)

AF:

0.0613

AC:

5290

AN:

86252

European-Finnish (FIN)

AF:

0.108

AC:

5745

AN:

53402

Middle Eastern (MID)

AF:

0.0896

AC:

517

AN:

5768

European-Non Finnish (NFE)

AF:

0.125

AC:

138834

AN:

1111796

Other (OTH)

AF:

0.144

AC:

8709

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

9463

18925

28388

37850

47313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5232

10464

15696

20928

26160

<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:

0.247

AC:

37540

AN:

151866

Hom.:

7921

Cov.:

AF XY:

0.240

AC XY:

17854

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.579

AC:

23903

AN:

41304

American (AMR)

AF:

0.193

AC:

2949

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0674

AC:

234

AN:

3470

East Asian (EAS)

AF:

0.0714

AC:

368

AN:

5156

South Asian (SAS)

AF:

0.0640

AC:

308

AN:

4816

European-Finnish (FIN)

AF:

0.0965

AC:

1022

AN:

10592

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8247

AN:

67944

Other (OTH)

AF:

0.214

AC:

451

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1097

2193

3290

4386

5483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.153

Hom.:

4200

Bravo

AF:

0.268

Asia WGS

AF:

0.137

AC:

475

AN:

3478

EpiCase

AF:

0.112

EpiControl

AF:

0.113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

IL4R-related disorder

Benign:1

Oct 28, 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

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.27

(source)

DANN

Benign

0.45

PhyloP100

-1.2

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