rs1805015

chr16-27362859-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000418.4(IL4R):c.1507T>C(p.Ser503Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,858 control chromosomes in the GnomAD database, including 25,776 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.22 (4428 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21348 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 0.124

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003134787).
• BP6: Variant 16-27362859-T-C is Benign according to our data. Variant chr16-27362859-T-C is described in ClinVar as [protective]. Clinvar id is 14667.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_benign, oryginal submission is: [protective].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4R	NM_000418.4	c.1507T>C	p.Ser503Pro	missense_variant	11/11	ENST00000395762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4R	ENST00000395762.7	c.1507T>C	p.Ser503Pro	missense_variant	11/11	1	NM_000418.4	P1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33005 AN: 151926 Hom.: 4411 Cov.: 32

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.0723

Gnomad SAS AF: 0.0990

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.205

GnomAD3 exomes AF: 0.159 AC: 39895 AN: 251224 Hom.: 3702 AF XY: 0.152 AC XY: 20640 AN XY: 135850

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0796

Gnomad SAS exome AF: 0.0968

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.165 AC: 241533 AN: 1461814 Hom.: 21348 Cov.: 35 AF XY: 0.162 AC XY: 117745 AN XY: 727222

Gnomad4 AFR exome AF: 0.383

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.0715

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.217 AC: 33065 AN: 152044 Hom.: 4428 Cov.: 32 AF XY: 0.211 AC XY: 15666 AN XY: 74344

Gnomad4 AFR AF: 0.380

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.0723

Gnomad4 SAS AF: 0.0985

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.204

Alfa AF: 0.168 Hom.: 5859

Bravo AF: 0.227

TwinsUK AF: 0.170 AC: 630

ALSPAC AF: 0.173 AC: 668

ESP6500AA AF: 0.363 AC: 1595

ESP6500EA AF: 0.162 AC: 1391

ExAC AF: 0.163 AC: 19843

Asia WGS AF: 0.131 AC: 456 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.152

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

RECLASSIFIED - POLYMORPHISM Benign:1

protective, no assertion criteria provided

literature only

OMIM

Oct 07, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.048	N
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.24	N;N;.
REVEL	Benign	0.085
Sift	Benign	0.27	T;T;.
Sift4G	Benign	0.12	T;T;T
Polyphen		0.54	P;P;.
Vest4		0.14
MPC		0.38
ClinPred		0.012	T
GERP RS		1.6
Varity_R		0.095
gMVP		0.20

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: rs1805015; hg19: chr16-27374180; COSMIC: COSV50142827; COSMIC: COSV50142827;