16-27358957-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000418.4(IL4R):c.812G>A(p.Arg271His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,613,870 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (5 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.687

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004656285).
• BP6: Variant 16-27358957-G-A is Benign according to our data. Variant chr16-27358957-G-A is described in ClinVar as [Benign]. Clinvar id is 708028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4R	NM_000418.4	c.812G>A	p.Arg271His	missense_variant	9/11	ENST00000395762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4R	ENST00000395762.7	c.812G>A	p.Arg271His	missense_variant	9/11	1	NM_000418.4	P1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00232 AC: 584 AN: 251444 Hom.: 2 AF XY: 0.00241 AC XY: 328 AN XY: 135898

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00721

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00274 AC: 4005 AN: 1461556 Hom.: 5 Cov.: 30 AF XY: 0.00278 AC XY: 2019 AN XY: 727092

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00818

Gnomad4 NFE exome AF: 0.00300

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74486

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00688

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00283 Hom.: 3

Bravo AF: 0.00192

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00241 AC: 293

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00249

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2017

- -

IL4R-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2020

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	0.069
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	8.7
Dann	Benign	0.18
DEOGEN2	Benign	0.075	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.51	N;N;.;.
MutationTaster	Benign	0.95	N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.14	N;N;.;.
REVEL	Benign	0.021
Sift	Benign	0.71	T;T;.;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;B;.;.
Vest4		0.13
MVP		0.24
MPC		0.16
ClinPred		0.0024	T
GERP RS		-0.67
Varity_R		0.046
gMVP		0.36

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: rs55988941; hg19: chr16-27370278;