rs2234900

chr16-27362651-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000418.4(IL4R):c.1299T>C(p.Leu433=) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.25 (7921 hom., cov: 31)
  • Exomes 𝑓: 0.13 (16829 hom.)
• Consequence: IL4R NM_000418.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.16

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 3056761.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
IL4R	NM_000418.4	c.1299T>C	p.Leu433=	synonymous_variant	11/11	ENST00000395762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4R	ENST00000395762.7	c.1299T>C	p.Leu433=	synonymous_variant	11/11	1	NM_000418.4	P1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37440 AN: 151748 Hom.: 7880 Cov.: 31

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

GnomAD3 exomes AF: 0.142 AC: 35650 AN: 250978 Hom.: 4389 AF XY: 0.129 AC XY: 17491 AN XY: 135658

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 SAS exome AF: 0.0587

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.: 35 AF XY: 0.126 AC XY: 91679 AN XY: 727130

Gnomad4 AFR exome AF: 0.599

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.0689

Gnomad4 EAS exome AF: 0.0711

Gnomad4 SAS exome AF: 0.0613

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.247 AC: 37540 AN: 151866 Hom.: 7921 Cov.: 31 AF XY: 0.240 AC XY: 17854 AN XY: 74244

Gnomad4 AFR AF: 0.579

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.0674

Gnomad4 EAS AF: 0.0714

Gnomad4 SAS AF: 0.0640

Gnomad4 FIN AF: 0.0965

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.214

Alfa AF: 0.148 Hom.: 3493

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: criteria provided, single submitter

Submissions by phenotype

IL4R-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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
Dann	Benign	0.45

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

Other links and lift over

dbSNP: rs2234900; hg19: chr16-27373972; COSMIC: COSV50144160; COSMIC: COSV50144160;