Genetic Variant IL33:p.Ile263Met (chr9-6256144-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033439.4(IL33):c.789C>G(p.Ile263Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,613,056 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 32 hom. )

Consequence

IL33
NM_033439.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.58

Publications

5 publications found

Variant links:

Genes affected

IL33 (HGNC:16028): (interleukin 33) The protein encoded by this gene is a cytokine that binds to the IL1RL1/ST2 receptor. The encoded protein is involved in the maturation of Th2 cells and the activation of mast cells, basophils, eosinophils and natural killer cells. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

IL33 links:

ENSG00000294323 (HGNC:):

ENSG00000294323 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002708286).

BP6

Variant 9-6256144-C-G is Benign according to our data. Variant chr9-6256144-C-G is described in ClinVar as Benign. ClinVar VariationId is 776409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1595/152126) while in subpopulation AFR AF = 0.0364 (1512/41506). AF 95% confidence interval is 0.0349. There are 24 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL33	NM_033439.4 link	c.789C>G	p.Ile263Met	missense_variant	Exon 8 of 8	ENST00000682010.1	NP_254274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL33	ENST00000682010.1 link	c.789C>G	p.Ile263Met	missense_variant	Exon 8 of 8		NM_033439.4	ENSP00000507310.1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1595

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00433

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00272

AC:

683

AN:

250884

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.0375

Gnomad AMR exome

AF:

0.00183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.00104

AC:

1513

AN:

1460930

Hom.:

Cov.:

AF XY:

0.000892

AC XY:

648

AN XY:

726786

show subpopulations

African (AFR)

AF:

0.0377

AC:

1260

AN:

33444

American (AMR)

AF:

0.00197

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1111408

Other (OTH)

AF:

0.00181

AC:

109

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.0105

AC:

1595

AN:

152126

Hom.:

Cov.:

AF XY:

0.00995

AC XY:

740

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0364

AC:

1512

AN:

41506

American (AMR)

AF:

0.00432

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67978

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

163

245

326

408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00176

Hom.:

Bravo

AF:

0.0117

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0300

AC:

132

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00347

AC:

421

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 12, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.64

CADD

Benign

6.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

.;.;T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.82

T;T;T;T

MetaRNN

Benign

0.0027

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;.;L;.

PhyloP100

-1.6

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

D;.;D;D

REVEL

Benign

0.095

Sift

Uncertain

0.0050

D;.;D;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

1.0

.;.;D;.

Vest4

0.23

MVP

0.15

MPC

0.028

ClinPred

0.073

GERP RS

-1.3

Varity_R

0.42

gMVP

0.17

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over