16-27362659-C-T

Position:

• chr16-27362659-C-T

Variant summary

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

The NM_000418.4(IL4R):​c.1307C>T​(p.Ser436Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,614,050 control chromosomes in the GnomAD database, including 1,594 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 0.036 (125 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1469 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51

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=0.0020773709).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL4R	NM_000418.4	c.1307C>T	p.Ser436Leu	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.1307C>T	p.Ser436Leu	missense_variant	11/11	1	NM_000418.4	ENSP00000379111.2

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5430 AN: 152066 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0735

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0383

GnomAD3 exomes AF: 0.0356 AC: 8935 AN: 250858 Hom.: 207 AF XY: 0.0370 AC XY: 5015 AN XY: 135604

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0704

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0382

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0465

GnomAD4 exome AF: 0.0427 AC: 62491 AN: 1461866 Hom.: 1469 Cov.: 35 AF XY: 0.0430 AC XY: 31297 AN XY: 727236

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0730

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0392

Gnomad4 FIN exome AF: 0.0301

Gnomad4 NFE exome AF: 0.0454

Gnomad4 OTH exome AF: 0.0452

GnomAD4 genome AF: 0.0357 AC: 5433 AN: 152184 Hom.: 125 Cov.: 32 AF XY: 0.0342 AC XY: 2547 AN XY: 74414

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.0735

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0340

Gnomad4 FIN AF: 0.0277

Gnomad4 NFE AF: 0.0435

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0428 Hom.: 198

Bravo AF: 0.0348

TwinsUK AF: 0.0399 AC: 148

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.0449 AC: 386

ExAC AF: 0.0360 AC: 4366

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0460

EpiControl AF: 0.0432

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.29
DANN	Benign	0.38
DEOGEN2	Benign	0.10	T;T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.69	.;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.23	N;N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.78	N;N;.
REVEL	Benign	0.068
Sift	Benign	0.46	T;T;.
Sift4G	Benign	0.23	T;T;T
Polyphen		0.014	B;B;.
Vest4		0.029
MPC		0.11
ClinPred		0.00030	T
GERP RS		-6.2
Varity_R		0.046
gMVP		0.072

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: rs1805013; hg19: chr16-27373980;