chr16-27344903-G-A

Position:

• chr16-27344903-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000418.4(IL4R):​c.244G>A​(p.Ala82Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,614,220 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A82V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0091 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (275 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.73

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=0.0023322105).
• BP6: Variant 16-27344903-G-A is Benign according to our data. Variant chr16-27344903-G-A is described in ClinVar as [Benign]. Clinvar id is 3043783.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0091 (1387/152368) while in subpopulation EAS AF= 0.0433 (225/5192). AF 95% confidence interval is 0.0387. There are 46 homozygotes in gnomad4. There are 937 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4R	NM_000418.4	c.244G>A	p.Ala82Thr	missense_variant	5/11	ENST00000395762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4R	ENST00000395762.7	c.244G>A	p.Ala82Thr	missense_variant	5/11	1	NM_000418.4	P1

Frequencies

GnomAD3 genomes AF: 0.00911 AC: 1387 AN: 152250 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0432

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0850

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0127 AC: 3191 AN: 251248 Hom.: 113 AF XY: 0.0119 AC XY: 1617 AN XY: 135784

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0371

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00555 AC: 8107 AN: 1461852 Hom.: 275 Cov.: 40 AF XY: 0.00541 AC XY: 3934 AN XY: 727226

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00631

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0506

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.0836

Gnomad4 NFE exome AF: 0.000796

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.00910 AC: 1387 AN: 152368 Hom.: 46 Cov.: 32 AF XY: 0.0126 AC XY: 937 AN XY: 74504

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0433

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0850

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00295 Hom.: 8

Bravo AF: 0.00299

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0111 AC: 1342

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

Aug 21, 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	0.068
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.0020
DANN	Benign	0.50
DEOGEN2	Benign	0.030	.;T;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.56	.;.;T;T;T
MetaRNN	Benign	0.0023	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.020	N;N;N;N;.
REVEL	Benign	0.014
Sift	Benign	0.81	T;T;T;T;.
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.13	.;B;B;.;.
Vest4		0.027, 0.030, 0.018
MPC		0.12
ClinPred		0.00097	T
GERP RS		-5.4
Varity_R		0.055
gMVP		0.28

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: rs144651842; hg19: chr16-27356224; COSMIC: COSV50146925; COSMIC: COSV50146925;