16-27344882-A-T

Variant names:

• chr16-27344882-A-T
• rs1805010
• NM_000418.4:c.223A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000418.4(IL4R):​c.223A>T​(p.Ile75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I75V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.221
• Publications: 281 publications found

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]

IL4R Gene-Disease associations (from GenCC):

• IgE responsiveness, atopic

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12045288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4	c.223A>T	p.Ile75Phe	missense_variant	Exon 5 of 11	ENST00000395762.7	NP_000409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL4R	ENST00000395762.7	c.223A>T	p.Ile75Phe	missense_variant	Exon 5 of 11	1	NM_000418.4	ENSP00000379111.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 46826

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.072	.;T;T;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.61	.;.;T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.22
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.6	D;N;N;D;.
REVEL	Benign	0.071
Sift	Uncertain	0.0040	D;T;T;D;.
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.65	.;P;P;.;.
Vest4		0.17, 0.17, 0.17
MutPred		0.16		Gain of catalytic residue at I75 (P = 0.1031);Gain of catalytic residue at I75 (P = 0.1031);Gain of catalytic residue at I75 (P = 0.1031);Gain of catalytic residue at I75 (P = 0.1031);.;
MVP		0.30
MPC		0.35
ClinPred		0.35	T
GERP RS		0.17
PromoterAI		0.032	Neutral
Varity_R		0.20
gMVP		0.44

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

Other links and lift over

dbSNP: rs1805010; hg19: chr16-27356203;