chr16-27346577-A-T

Position:

• chr16-27346577-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000418.4(IL4R):​c.472A>T​(p.Thr158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: IL4R NM_000418.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.268

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27656582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL4R	NM_000418.4	c.472A>T	p.Thr158Ser	missense_variant	6/11	ENST00000395762.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL4R	ENST00000395762.7	c.472A>T	p.Thr158Ser	missense_variant	6/11	1	NM_000418.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458440 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.472A>T (p.T158S) alteration is located in exon 6 (coding exon 4) of the IL4R gene. This alteration results from a A to T substitution at nucleotide position 472, causing the threonine (T) at amino acid position 158 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.29
DANN	Benign	0.39
DEOGEN2	Benign	0.090	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.49	.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.94	N;N;.
REVEL	Benign	0.081
Sift	Benign	0.30	T;T;.
Sift4G	Benign	0.33	T;T;T
Polyphen		0.026	B;B;.
Vest4		0.080
MutPred		0.56		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;
MVP		0.59
MPC		0.12
ClinPred		0.053	T
GERP RS		-0.39
Varity_R		0.28
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2085652504; hg19: chr16-27357898;