dbSNP rs3024638: IL4R:p.Thr256Thr (chr16-27355905-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000418.4(IL4R):c.768C>G(p.Thr256Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,609,190 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T256T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 102 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 106 hom. )

Consequence

IL4R
NM_000418.4 splice_region, synonymous

Scores

Splicing: ADA: 0.002463

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.27

Publications

7 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 16-27355905-C-G is Benign according to our data. Variant chr16-27355905-C-G is described in ClinVar as Benign. ClinVar VariationId is 768763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0644 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	UniProt
IL4R	NM_000418.4	MANE Select	c.768C>G	p.Thr256Thr	splice_region synonymous	Exon 8 of 11	NP_000409.1	P24394-1
IL4R	NM_001257406.2		c.768C>G	p.Thr256Thr	splice_region synonymous	Exon 7 of 10	NP_001244335.1	P24394-1
IL4R	NM_001257407.2		c.723C>G	p.Thr241Thr	splice_region synonymous	Exon 8 of 11	NP_001244336.1	P24394-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL4R	ENST00000395762.7	TSL:1 MANE Select	c.768C>G	p.Thr256Thr	splice_region synonymous	Exon 8 of 11	ENSP00000379111.2	P24394-1
IL4R	ENST00000543915.6	TSL:1	c.768C>G	p.Thr256Thr	splice_region synonymous	Exon 7 of 10	ENSP00000441667.2	P24394-1
IL4R	ENST00000912076.1		c.789C>G	p.Thr263Thr	splice_region synonymous	Exon 7 of 10	ENSP00000582135.1

Frequencies

GnomAD3 genomes

AF:

0.0202

AC:

3066

AN:

152086

Hom.:

100

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0659

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.00654

AC:

1639

AN:

250720

AF XY:

0.00507

show subpopulations

Gnomad AFR exome

AF:

0.0643

Gnomad AMR exome

AF:

0.00752

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.00751

GnomAD4 exome

AF:

0.00315

AC:

4588

AN:

1456986

Hom.:

106

Cov.:

AF XY:

0.00287

AC XY:

2084

AN XY:

725102

show subpopulations

African (AFR)

AF:

0.0702

AC:

2343

AN:

33362

American (AMR)

AF:

0.00765

AC:

342

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0108

AC:

282

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.000313

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52624

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000954

AC:

1057

AN:

1108372

Other (OTH)

AF:

0.00789

AC:

475

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

215

431

646

862

1077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.0203

AC:

3094

AN:

152204

Hom.:

102

Cov.:

AF XY:

0.0198

AC XY:

1477

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0664

AC:

2757

AN:

41500

American (AMR)

AF:

0.0105

AC:

161

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

68010

Other (OTH)

AF:

0.0204

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

146

292

437

583

729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00754

Hom.:

Bravo

AF:

0.0231

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00261

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=84/16

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0025

dbscSNV1_RF

Benign

0.12

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

Computational scores

Splicing

Publications

Other links and lift over