5-132679879-C-G

Position:

• chr5-132679879-C-G

Variant summary

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

The NM_000589.4(IL4):​c.349C>G​(p.Leu117Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,726 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IL4 NM_000589.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.298

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]

LOC105379176 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL4	NM_000589.4	c.349C>G	p.Leu117Val	missense_variant	3/4	ENST00000231449.7	NP_000580.1
IL4	NM_172348.3	c.301C>G	p.Leu101Val	missense_variant	2/3		NP_758858.1
IL4	NM_001354990.2	c.*39C>G		3_prime_UTR_variant	4/5		NP_001341919.1
LOC105379176	NR_134248.1	n.414G>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL4	ENST00000231449.7	c.349C>G	p.Leu117Val	missense_variant	3/4	1	NM_000589.4	ENSP00000231449.2
IL4	ENST00000350025.2	c.301C>G	p.Leu101Val	missense_variant	2/3	1		ENSP00000325190.3
IL4	ENST00000622422.1	c.*39C>G		3_prime_UTR_variant	4/5	1		ENSP00000480581.1
IL4	ENST00000495905.1	n.*10C>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459726 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 14, 2023

The c.349C>G (p.L117V) alteration is located in exon 3 (coding exon 3) of the IL4 gene. This alteration results from a C to G substitution at nucleotide position 349, causing the leucine (L) at amino acid position 117 to be replaced by a valine (V). 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	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.92
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.017	B;.
Vest4		0.25
MutPred		0.79		Loss of helix (P = 0.0558);.;
MVP		0.31
MPC		0.33
ClinPred		0.41	T
GERP RS		-7.7
Varity_R		0.32
gMVP		0.12

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: rs1231414018; hg19: chr5-132015571;