NM_000418.4:c.437C>G

Variant names:

• chr16-27346542-C-G
• rs139150588
• NM_000418.4:c.437C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000418.4(IL4R):​c.437C>G​(p.Pro146Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P146L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.200
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39556646).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000418.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL4R	NM_000418.4	MANE Select	c.437C>G	p.Pro146Arg	missense	Exon 6 of 11	NP_000409.1	P24394-1
	IL4R	NM_001257406.2		c.437C>G	p.Pro146Arg	missense	Exon 5 of 10	NP_001244335.1	P24394-1
	IL4R	NM_001257407.2		c.392C>G	p.Pro131Arg	missense	Exon 6 of 11	NP_001244336.1	P24394-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL4R	ENST00000395762.7	TSL:1 MANE Select	c.437C>G	p.Pro146Arg	missense	Exon 6 of 11	ENSP00000379111.2	P24394-1
	IL4R	ENST00000543915.6	TSL:1	c.437C>G	p.Pro146Arg	missense	Exon 5 of 10	ENSP00000441667.2	P24394-1
	IL4R	ENST00000912076.1		c.458C>G	p.Pro153Arg	missense	Exon 5 of 10	ENSP00000582135.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461748 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111888

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.20
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.57		Gain of solvent accessibility (P = 0.0584)
MVP		0.81
MPC		0.60
ClinPred		0.80	D
GERP RS		1.5
Varity_R		0.38
gMVP		0.70
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs139150588; hg19: chr16-27357863;