NM_000418.4:c.1199A>C

Variant names:

• chr16-27362551-A-C
• rs1805011
• NM_000418.4:c.1199A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000418.4(IL4R):​c.1199A>C​(p.Glu400Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,858 control chromosomes in the GnomAD database, including 21,456 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (6779 hom., cov: 32)
  • Exomes 𝑓: 0.12 (14677 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.336
• Publications: 105 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.359906E-5).
• BP6: Variant 16-27362551-A-C is Benign according to our data. Variant chr16-27362551-A-C is described in ClinVar as Benign. ClinVar VariationId is 3056511.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

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.1199A>C	p.Glu400Ala	missense	Exon 11 of 11	NP_000409.1	P24394-1
	IL4R	NM_001257406.2		c.1199A>C	p.Glu400Ala	missense	Exon 10 of 10	NP_001244335.1	P24394-1
	IL4R	NM_001257407.2		c.1154A>C	p.Glu385Ala	missense	Exon 11 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.1199A>C	p.Glu400Ala	missense	Exon 11 of 11	ENSP00000379111.2	P24394-1
	IL4R	ENST00000543915.6	TSL:1	c.1199A>C	p.Glu400Ala	missense	Exon 10 of 10	ENSP00000441667.2	P24394-1
	IL4R	ENST00000912076.1		c.1220A>C	p.Glu407Ala	missense	Exon 10 of 10	ENSP00000582135.1

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34760 AN: 151906 Hom.: 6755 Cov.: 32

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.0719

Gnomad SAS AF: 0.0625

Gnomad FIN AF: 0.0958

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.133 AC: 33353 AN: 251354 AF XY: 0.120

Gnomad AFR exome AF: 0.547

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.0798

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.122 AC: 178998 AN: 1461834 Hom.: 14677 Cov.: 35 AF XY: 0.118 AC XY: 85897 AN XY: 727214

African (AFR) AF: 0.551 AC: 18436 AN: 33476

American (AMR) AF: 0.151 AC: 6743 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 1476 AN: 26136

East Asian (EAS) AF: 0.0713 AC: 2830 AN: 39700

South Asian (SAS) AF: 0.0584 AC: 5040 AN: 86256

European-Finnish (FIN) AF: 0.106 AC: 5672 AN: 53416

Middle Eastern (MID) AF: 0.0725 AC: 418 AN: 5766

European-Non Finnish (NFE) AF: 0.117 AC: 130308 AN: 1111964

Other (OTH) AF: 0.134 AC: 8075 AN: 60396

GnomAD4 genome AF: 0.229 AC: 34839 AN: 152024 Hom.: 6779 Cov.: 32 AF XY: 0.223 AC XY: 16613 AN XY: 74338

African (AFR) AF: 0.533 AC: 22040 AN: 41364

American (AMR) AF: 0.181 AC: 2760 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

East Asian (EAS) AF: 0.0719 AC: 371 AN: 5162

South Asian (SAS) AF: 0.0621 AC: 300 AN: 4830

European-Finnish (FIN) AF: 0.0958 AC: 1017 AN: 10616

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7707 AN: 67996

Other (OTH) AF: 0.197 AC: 414 AN: 2104

Alfa AF: 0.139 Hom.: 8373

Bravo AF: 0.248

TwinsUK AF: 0.125 AC: 462

ALSPAC AF: 0.122 AC: 471

ESP6500AA AF: 0.525 AC: 2307

ESP6500EA AF: 0.112 AC: 961

ExAC AF: 0.140 AC: 16954

Asia WGS AF: 0.132 AC: 459 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.103

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	IL4R-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.2
DANN	Benign	0.82
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.000094	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.64	N
PhyloP100		0.34
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.052
Sift	Benign	0.36	T
Sift4G	Benign	0.24	T
Polyphen		0.43	B
Vest4		0.087
MPC		0.18
ClinPred		0.0085	T
GERP RS		0.21
Varity_R		0.064
gMVP		0.40
Mutation Taster		=98/2	polymorphism (auto)

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: rs1805011; hg19: chr16-27373872; COSMIC: COSV50139875; COSMIC: COSV50139875;