5-132679831-A-C

Position:

• chr5-132679831-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000589.4(IL4):​c.301A>C​(p.Lys101Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL4 NM_000589.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.487

Genes affected

IL4 (HGNC:6014): (interleukin 4) The protein encoded by this gene is a pleiotropic cytokine produced by activated T cells. This cytokine is a ligand for interleukin 4 receptor. The interleukin 4 receptor also binds to IL13, which may contribute to many overlapping functions of this cytokine and IL13. STAT6, a signal transducer and activator of transcription, has been shown to play a central role in mediating the immune regulatory signal of this cytokine. This gene, IL3, IL5, IL13, and CSF2 form a cytokine gene cluster on chromosome 5q, with this gene particularly close to IL13. This gene, IL13 and IL5 are found to be regulated coordinately by several long-range regulatory elements in an over 120 kilobase range on the chromosome. IL4 is considered an important cytokine for tissue repair, counterbalancing the effects of proinflammatory type 1 cytokines, however, it also promotes allergic airway inflammation. Moreover, IL-4, a type 2 cytokine, mediates and regulates a variety of human host responses such as allergic, anti-parasitic, wound healing, and acute inflammation. This cytokine has been reported to promote resolution of neutrophil-mediated acute lung injury. In an allergic response, IL-4 has an essential role in the production of allergen-specific immunoglobin (Ig) E. This pro-inflammatory cytokine has been observed to be increased in COVID-19 (Coronavirus disease 2019) patients, but is not necessarily associated with severe COVID-19 pathology. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Aug 2020]

IL4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070822924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL4	NM_000589.4	c.301A>C	p.Lys101Gln	missense_variant	3/4	ENST00000231449.7	NP_000580.1
IL4	NM_172348.3	c.253A>C	p.Lys85Gln	missense_variant	2/3		NP_758858.1
IL4	NM_001354990.2	c.402A>C	p.Thr134Thr	synonymous_variant	4/5		NP_001341919.1
LOC105379176	NR_134248.1	n.462T>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL4	ENST00000231449.7	c.301A>C	p.Lys101Gln	missense_variant	3/4	1	NM_000589.4	ENSP00000231449.2
IL4	ENST00000350025.2	c.253A>C	p.Lys85Gln	missense_variant	2/3	1		ENSP00000325190.3
IL4	ENST00000622422.1	c.402A>C	p.Thr134Thr	synonymous_variant	4/5	1		ENSP00000480581.1
IL4	ENST00000495905.1	n.267A>C		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Feb 28, 2023

The c.301A>C (p.K101Q) alteration is located in exon 3 (coding exon 3) of the IL4 gene. This alteration results from a A to C substitution at nucleotide position 301, causing the lysine (K) at amino acid position 101 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.18
DANN	Benign	0.72
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.24	N;N
REVEL	Benign	0.026
Sift	Benign	0.47	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0010	B;.
Vest4		0.14
MutPred		0.52		Loss of catalytic residue at K101 (P = 0.0341);.;
MVP		0.33
MPC		0.33
ClinPred		0.16	T
GERP RS		-4.5
Varity_R		0.39
gMVP		0.10

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-132015523;