Genetic Variant IL4:p.Asp111Asp (chr5-132679863-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000589.4(IL4):c.333C>T(p.Asp111Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00752 in 1,613,550 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 67 hom. )

Consequence

IL4
NM_000589.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.292

Publications

7 publications found

Variant links:

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 links:

LOC105379176 (HGNC:):

LOC105379176 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 5-132679863-C-T is Benign according to our data. Variant chr5-132679863-C-T is described in ClinVar as Benign. ClinVar VariationId is 782744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.292 with no splicing effect.

BS2

High AC in GnomAd4 at 932 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000589.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL4	NM_000589.4	MANE Select	c.333C>T	p.Asp111Asp	synonymous	Exon 3 of 4	NP_000580.1	P05112-1
IL4	NM_172348.3		c.285C>T	p.Asp95Asp	synonymous	Exon 2 of 3	NP_758858.1	Q5FC01
IL4	NM_001354990.2		c.*23C>T		3_prime_UTR	Exon 4 of 5	NP_001341919.1	U3LVN1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL4	ENST00000231449.7	TSL:1 MANE Select	c.333C>T	p.Asp111Asp	synonymous	Exon 3 of 4	ENSP00000231449.2	P05112-1
IL4	ENST00000350025.2	TSL:1	c.285C>T	p.Asp95Asp	synonymous	Exon 2 of 3	ENSP00000325190.3	P05112-2
IL4	ENST00000622422.1	TSL:1	c.*23C>T		3_prime_UTR	Exon 4 of 5	ENSP00000480581.1	U3LVN1

Frequencies

GnomAD3 genomes

AF:

0.00611

AC:

930

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00923

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00688

AC:

1717

AN:

249456

AF XY:

0.00760

show subpopulations

Gnomad AFR exome

AF:

0.00119

Gnomad AMR exome

AF:

0.00354

Gnomad ASJ exome

AF:

0.00479

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.00925

Gnomad OTH exome

AF:

0.00721

GnomAD4 exome

AF:

0.00767

AC:

11205

AN:

1461212

Hom.:

Cov.:

AF XY:

0.00791

AC XY:

5748

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

33466

American (AMR)

AF:

0.00363

AC:

162

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00448

AC:

117

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0136

AC:

1175

AN:

86200

European-Finnish (FIN)

AF:

0.00345

AC:

183

AN:

53116

Middle Eastern (MID)

AF:

0.0175

AC:

101

AN:

5758

European-Non Finnish (NFE)

AF:

0.00804

AC:

8935

AN:

1111810

Other (OTH)

AF:

0.00794

AC:

479

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

585

1170

1754

2339

2924

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00612

AC:

932

AN:

152338

Hom.:

Cov.:

AF XY:

0.00588

AC XY:

438

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41576

American (AMR)

AF:

0.00621

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0120

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00923

AC:

628

AN:

68040

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00796

Hom.:

Bravo

AF:

0.00522

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.00949

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.2

(source)

DANN

Benign

0.54

PhyloP100

0.29

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over