16-27342158-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000418.4(IL4R):c.108C>T(p.Ser36=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,190 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 32)
  • Exomes 𝑓: 0.013 (147 hom.)
• Consequence: IL4R NM_000418.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.92

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-27342158-C-T is Benign according to our data. Variant chr16-27342158-C-T is described in ClinVar as [Benign]. Clinvar id is 771761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4R	NM_000418.4	c.108C>T	p.Ser36=	synonymous_variant	4/11	ENST00000395762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4R	ENST00000395762.7	c.108C>T	p.Ser36=	synonymous_variant	4/11	1	NM_000418.4	P1

Frequencies

GnomAD3 genomes AF: 0.00999 AC: 1521 AN: 152214 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00993 AC: 2497 AN: 251446 Hom.: 18 AF XY: 0.0103 AC XY: 1394 AN XY: 135900

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00911

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00493

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0130 AC: 19071 AN: 1461858 Hom.: 147 Cov.: 31 AF XY: 0.0128 AC XY: 9303 AN XY: 727232

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.00912

Gnomad4 ASJ exome AF: 0.0297

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00508

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.00999 AC: 1522 AN: 152332 Hom.: 20 Cov.: 32 AF XY: 0.00990 AC XY: 737 AN XY: 74478

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0129 Hom.: 9

Bravo AF: 0.0105

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0166

EpiControl AF: 0.0176

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2018

- -

IL4R-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 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	-0.79
Cadd	Benign	4.8
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17548704; hg19: chr16-27353479; COSMIC: COSV50166065; COSMIC: COSV50166065;