rs1805011

Positions:

• chr16-27362551-A-C
• chr16-27362551-A-G
• chr16-27362551-A-T

Variant summary

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

The NM_000418.4(IL4R):​c.1199A>C​(p.Glu400Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,858 control chromosomes in the GnomAD database, including 21,456 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (6779 hom., cov: 32)
  • Exomes 𝑓: 0.12 (14677 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.336

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=9.359906E-5).
• BP6: Variant 16-27362551-A-C is Benign according to our data. Variant chr16-27362551-A-C is described in ClinVar as [Benign]. Clinvar id is 3056511.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL4R	NM_000418.4	c.1199A>C	p.Glu400Ala	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.1199A>C	p.Glu400Ala	missense_variant	11/11	1	NM_000418.4	ENSP00000379111	P1

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34760 AN: 151906 Hom.: 6755 Cov.: 32

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.0719

Gnomad SAS AF: 0.0625

Gnomad FIN AF: 0.0958

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.133 AC: 33353 AN: 251354 Hom.: 3795 AF XY: 0.120 AC XY: 16343 AN XY: 135854

Gnomad AFR exome AF: 0.547

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.0798

Gnomad SAS exome AF: 0.0558

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.122 AC: 178998 AN: 1461834 Hom.: 14677 Cov.: 35 AF XY: 0.118 AC XY: 85897 AN XY: 727214

Gnomad4 AFR exome AF: 0.551

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.0565

Gnomad4 EAS exome AF: 0.0713

Gnomad4 SAS exome AF: 0.0584

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.229 AC: 34839 AN: 152024 Hom.: 6779 Cov.: 32 AF XY: 0.223 AC XY: 16613 AN XY: 74338

Gnomad4 AFR AF: 0.533

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.0541

Gnomad4 EAS AF: 0.0719

Gnomad4 SAS AF: 0.0621

Gnomad4 FIN AF: 0.0958

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.197

Alfa AF: 0.119 Hom.: 2490

Bravo AF: 0.248

TwinsUK AF: 0.125 AC: 462

ALSPAC AF: 0.122 AC: 471

ESP6500AA AF: 0.525 AC: 2307

ESP6500EA AF: 0.112 AC: 961

ExAC AF: 0.140 AC: 16954

Asia WGS AF: 0.132 AC: 459 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.103

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

IL4R-related disorder Benign:1

Benign, no assertion criteria provided

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.2
DANN	Benign	0.82
DEOGEN2	Benign	0.16	T;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.65	.;T;T
MetaRNN	Benign	0.000094	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.64	N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Benign	0.052
Sift	Benign	0.36	T;T;.
Sift4G	Benign	0.24	T;T;T
Polyphen		0.43	B;B;.
Vest4		0.087
MPC		0.18
ClinPred		0.0085	T
GERP RS		0.21
Varity_R		0.064
gMVP		0.40

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: rs1805011; hg19: chr16-27373872; COSMIC: COSV50139875; COSMIC: COSV50139875;