5-132682556-T-A

Variant names:

• chr5-132682556-T-A
• NM_000589.4:c.431T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000589.4(IL4):​c.431T>A​(p.Met144Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IL4 NM_000589.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.879

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL4	NM_000589.4	c.431T>A	p.Met144Lys	missense_variant	Exon 4 of 4	ENST00000231449.7	NP_000580.1
IL4	NM_172348.3	c.383T>A	p.Met128Lys	missense_variant	Exon 3 of 3		NP_758858.1
IL4	NM_001354990.2	c.*121T>A		3_prime_UTR_variant	Exon 5 of 5		NP_001341919.1
LOC105379176	NR_134248.1	n.74A>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL4	ENST00000231449.7	c.431T>A	p.Met144Lys	missense_variant	Exon 4 of 4	1	NM_000589.4	ENSP00000231449.2
IL4	ENST00000350025.2	c.383T>A	p.Met128Lys	missense_variant	Exon 3 of 3	1		ENSP00000325190.3
IL4	ENST00000622422.1	c.*121T>A		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000480581.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456192 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 724678

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;.
Eigen	Benign	0.14
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.99	D;.
Vest4		0.74
MutPred		0.81		Gain of disorder (P = 0.0068);.;
MVP		0.86
MPC		1.3
ClinPred		0.89	D
GERP RS		2.7
Varity_R		0.87
gMVP		0.57

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: chr5-132018248;