rs3024678

Positions:

• chr16-27363375-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000395762.7(IL4R):​c.2023C>T​(p.Pro675Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0183 in 1,614,158 control chromosomes in the GnomAD database, including 352 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.012 (13 hom., cov: 33)
  • Exomes 𝑓: 0.019 (339 hom.)
• Consequence: IL4R ENST00000395762.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.557

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=0.0051090717).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0116 (1772/152314) while in subpopulation NFE AF= 0.0202 (1376/68004). AF 95% confidence interval is 0.0193. There are 13 homozygotes in gnomad4. There are 744 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL4R	NM_000418.4	c.2023C>T	p.Pro675Ser	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.2023C>T	p.Pro675Ser	missense_variant	11/11	1	NM_000418.4	ENSP00000379111	P1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1772 AN: 152196 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0113 AC: 2836 AN: 251080 Hom.: 32 AF XY: 0.0115 AC XY: 1567 AN XY: 135776

Gnomad AFR exome AF: 0.00327

Gnomad AMR exome AF: 0.00697

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00412

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0190 AC: 27796 AN: 1461844 Hom.: 339 Cov.: 34 AF XY: 0.0185 AC XY: 13443 AN XY: 727224

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00722

Gnomad4 ASJ exome AF: 0.00490

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00508

Gnomad4 FIN exome AF: 0.00260

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0181

GnomAD4 genome AF: 0.0116 AC: 1772 AN: 152314 Hom.: 13 Cov.: 33 AF XY: 0.00999 AC XY: 744 AN XY: 74466

Gnomad4 AFR AF: 0.00370

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0202

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.0176 Hom.: 40

Bravo AF: 0.0127

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.00478 AC: 21

ESP6500EA AF: 0.0201 AC: 173

ExAC AF: 0.0108 AC: 1316

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.0
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.79	.;T;T
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	0.62	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Benign	0.10
Sift	Uncertain	0.0060	D;D;.
Sift4G	Benign	0.38	T;T;T
Polyphen		0.83	P;P;.
Vest4		0.064
MPC		0.16
ClinPred		0.024	T
GERP RS		3.4
Varity_R		0.063
gMVP		0.15

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: rs3024678; hg19: chr16-27374696;