rs1805012

chr16-27362643-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000418.4(IL4R):c.1291T>C(p.Cys431Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,770 control chromosomes in the GnomAD database, including 9,531 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.098 (783 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8748 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.538

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018278062).
• BP6: Variant 16-27362643-T-C is Benign according to our data. Variant chr16-27362643-T-C is described in ClinVar as [Benign]. Clinvar id is 3056489.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4R	NM_000418.4	c.1291T>C	p.Cys431Arg	missense_variant	11/11	ENST00000395762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4R	ENST00000395762.7	c.1291T>C	p.Cys431Arg	missense_variant	11/11	1	NM_000418.4	P1

Frequencies

GnomAD3 genomes AF: 0.0980 AC: 14904 AN: 152008 Hom.: 783 Cov.: 32

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.0708

Gnomad SAS AF: 0.0595

Gnomad FIN AF: 0.0950

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0967

GnomAD3 exomes AF: 0.0961 AC: 24132 AN: 251120 Hom.: 1217 AF XY: 0.0930 AC XY: 12625 AN XY: 135738

Gnomad AFR exome AF: 0.0825

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0448

Gnomad EAS exome AF: 0.0792

Gnomad SAS exome AF: 0.0554

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0895

GnomAD4 exome AF: 0.107 AC: 156484 AN: 1461644 Hom.: 8748 Cov.: 35 AF XY: 0.105 AC XY: 76058 AN XY: 727114

Gnomad4 AFR exome AF: 0.0859

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.0452

Gnomad4 EAS exome AF: 0.0710

Gnomad4 SAS exome AF: 0.0579

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.0976

GnomAD4 genome AF: 0.0980 AC: 14910 AN: 152126 Hom.: 783 Cov.: 32 AF XY: 0.0961 AC XY: 7146 AN XY: 74370

Gnomad4 AFR AF: 0.0855

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.0430

Gnomad4 EAS AF: 0.0708

Gnomad4 SAS AF: 0.0595

Gnomad4 FIN AF: 0.0950

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.0961

Alfa AF: 0.101 Hom.: 1245

Bravo AF: 0.0968

TwinsUK AF: 0.118 AC: 439

ALSPAC AF: 0.119 AC: 458

ESP6500AA AF: 0.0890 AC: 391

ESP6500EA AF: 0.108 AC: 925

ExAC AF: 0.0956 AC: 11606

Asia WGS AF: 0.0930 AC: 322 AN: 3478

EpiCase AF: 0.0973

EpiControl AF: 0.0976

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

IL4R-related condition Benign:1

Benign, criteria provided, single submitter

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	0.13
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	9.7
Dann	Benign	0.90
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.061	N
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Benign	0.074
Sift	Benign	0.078	T;T;.
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.11
MPC		0.23
ClinPred		0.048	T
GERP RS		0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
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: rs1805012; hg19: chr16-27373964; COSMIC: COSV50140670; COSMIC: COSV50140670;