rs1805014

Positions:

• chr16-27363708-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000418.4(IL4R):​c.2356T>C​(p.Ser786Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00776 in 1,613,810 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (56 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.36

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003879249).
• BP6: Variant 16-27363708-T-C is Benign according to our data. Variant chr16-27363708-T-C is described in ClinVar as [Benign]. Clinvar id is 779011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1991/152152) while in subpopulation AFR AF= 0.03 (1243/41492). AF 95% confidence interval is 0.0286. There are 19 homozygotes in gnomad4. There are 921 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL4R	NM_000418.4	c.2356T>C	p.Ser786Pro	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.2356T>C	p.Ser786Pro	missense_variant	11/11	1	NM_000418.4	ENSP00000379111	P1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1974 AN: 152034 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00771

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00744 AC: 1869 AN: 251142 Hom.: 13 AF XY: 0.00703 AC XY: 954 AN XY: 135778

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00943

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00849

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00720 AC: 10531 AN: 1461658 Hom.: 56 Cov.: 34 AF XY: 0.00707 AC XY: 5143 AN XY: 727148

Gnomad4 AFR exome AF: 0.0283

Gnomad4 AMR exome AF: 0.00608

Gnomad4 ASJ exome AF: 0.00987

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00220

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00746

Gnomad4 OTH exome AF: 0.00730

GnomAD4 genome AF: 0.0131 AC: 1991 AN: 152152 Hom.: 19 Cov.: 32 AF XY: 0.0124 AC XY: 921 AN XY: 74400

Gnomad4 AFR AF: 0.0300

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00771

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00891 Hom.: 12

Bravo AF: 0.0144

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00809 AC: 982

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00865

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	.;T;T
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N;N;.
REVEL	Benign	0.096
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.53	P;P;.
Vest4		0.22
MVP		0.32
MPC		0.19
ClinPred		0.012	T
GERP RS		3.8
Varity_R		0.27
gMVP		0.072

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: rs1805014; hg19: chr16-27375029; COSMIC: COSV50144363; COSMIC: COSV50144363;