16-27352627-G-T

Variant names:

• chr16-27352627-G-T
• rs987774304
• NM_000418.4:c.601G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000418.4(IL4R):​c.601G>T​(p.Val201Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4R	NM_000418.4	c.601G>T	p.Val201Leu	missense_variant	Exon 7 of 11	ENST00000395762.7	NP_000409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL4R	ENST00000395762.7	c.601G>T	p.Val201Leu	missense_variant	Exon 7 of 11	1	NM_000418.4	ENSP00000379111.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	2.9	M;M;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	N;N;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.018	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.86	P;P;.
Vest4		0.59
MutPred		0.54		Loss of methylation at R198 (P = 0.1228);Loss of methylation at R198 (P = 0.1228);.;
MVP		0.88
MPC		0.32
ClinPred		0.96	D
GERP RS		3.9
Varity_R		0.54
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs987774304; hg19: chr16-27363948;