16-27355905-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000418.4(IL4R):c.768C>G(p.Thr256=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,609,190 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (102 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (106 hom.)
• Consequence: IL4R NM_000418.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.002463
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.27

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-27355905-C-G is Benign according to our data. Variant chr16-27355905-C-G is described in ClinVar as [Benign]. Clinvar id is 768763.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4R	NM_000418.4	c.768C>G	p.Thr256=	splice_region_variant, synonymous_variant	8/11	ENST00000395762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4R	ENST00000395762.7	c.768C>G	p.Thr256=	splice_region_variant, synonymous_variant	8/11	1	NM_000418.4	P1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3066 AN: 152086 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.0659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00654 AC: 1639 AN: 250720 Hom.: 33 AF XY: 0.00507 AC XY: 687 AN XY: 135588

Gnomad AFR exome AF: 0.0643

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00751

GnomAD4 exome AF: 0.00315 AC: 4588 AN: 1456986 Hom.: 106 Cov.: 29 AF XY: 0.00287 AC XY: 2084 AN XY: 725102

Gnomad4 AFR exome AF: 0.0702

Gnomad4 AMR exome AF: 0.00765

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000954

Gnomad4 OTH exome AF: 0.00789

GnomAD4 genome AF: 0.0203 AC: 3094 AN: 152204 Hom.: 102 Cov.: 32 AF XY: 0.0198 AC XY: 1477 AN XY: 74426

Gnomad4 AFR AF: 0.0664

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.00754 Hom.: 9

Bravo AF: 0.0231

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00261

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	13
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.12
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: rs3024638; hg19: chr16-27367226;