rs1805016

Positions:

• chr16-27363606-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000418.4(IL4R):​c.2254T>G​(p.Ser752Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0647 in 1,613,744 control chromosomes in the GnomAD database, including 6,244 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (2257 hom., cov: 32)
  • Exomes 𝑓: 0.059 (3987 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.786

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003445685).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL4R	NM_000418.4	c.2254T>G	p.Ser752Ala	missense_variant	11/11	ENST00000395762.7	NP_000409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL4R	ENST00000395762.7	c.2254T>G	p.Ser752Ala	missense_variant	11/11	1	NM_000418.4	ENSP00000379111.2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18643 AN: 151956 Hom.: 2246 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0708

Gnomad ASJ AF: 0.0899

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0382

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0528

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.0637 AC: 15957 AN: 250646 Hom.: 1149 AF XY: 0.0591 AC XY: 8019 AN XY: 135682

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.0401

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0410

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.0549

Gnomad OTH exome AF: 0.0687

GnomAD4 exome AF: 0.0587 AC: 85792 AN: 1461672 Hom.: 3987 Cov.: 34 AF XY: 0.0579 AC XY: 42102 AN XY: 727152

Gnomad4 AFR exome AF: 0.325

Gnomad4 AMR exome AF: 0.0446

Gnomad4 ASJ exome AF: 0.0895

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.0318

Gnomad4 NFE exome AF: 0.0541

Gnomad4 OTH exome AF: 0.0728

GnomAD4 genome AF: 0.123 AC: 18690 AN: 152072 Hom.: 2257 Cov.: 32 AF XY: 0.118 AC XY: 8764 AN XY: 74336

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.0706

Gnomad4 ASJ AF: 0.0899

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0382

Gnomad4 FIN AF: 0.0294

Gnomad4 NFE AF: 0.0528

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0629 Hom.: 894

Bravo AF: 0.133

TwinsUK AF: 0.0523 AC: 194

ALSPAC AF: 0.0568 AC: 219

ESP6500AA AF: 0.305 AC: 1342

ESP6500EA AF: 0.0538 AC: 463

ExAC AF: 0.0687 AC: 8342

Asia WGS AF: 0.0390 AC: 136 AN: 3478

EpiCase AF: 0.0581

EpiControl AF: 0.0558

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.90
DANN	Benign	0.93
DEOGEN2	Benign	0.15	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.42	.;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.84	N;N;.
REVEL	Benign	0.040
Sift	Benign	0.12	T;T;.
Sift4G	Benign	0.094	T;T;T
Polyphen		0.18	B;B;.
Vest4		0.066
MPC		0.12
ClinPred		0.0012	T
GERP RS		-4.4
Varity_R		0.049
gMVP		0.058

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: rs1805016; hg19: chr16-27374927; COSMIC: COSV50142283; COSMIC: COSV50142283;