rs16924241

Variant names:

• chr9-6256144-C-G
• rs16924241
• NM_033439.4:c.789C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.58
• Publications: 5 publications found

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]

ENSG00000294323 (HGNC:):

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033439.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL33	NM_033439.4	MANE Select	c.789C>G	p.Ile263Met	missense	Exon 8 of 8	NP_254274.1	O95760-1
	IL33	NM_001314044.2		c.789C>G	p.Ile263Met	missense	Exon 8 of 8	NP_001300973.1	O95760-1
	IL33	NM_001314045.2		c.789C>G	p.Ile263Met	missense	Exon 8 of 8	NP_001300974.1	O95760-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL33	ENST00000682010.1	MANE Select	c.789C>G	p.Ile263Met	missense	Exon 8 of 8	ENSP00000507310.1	O95760-1
	IL33	ENST00000381434.7	TSL:1	c.789C>G	p.Ile263Met	missense	Exon 7 of 7	ENSP00000370842.3	O95760-1
	IL33	ENST00000611532.4	TSL:1	c.663C>G	p.Ile221Met	missense	Exon 6 of 6	ENSP00000478858.1	O95760-3

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1595 AN: 152008 Hom.: 24 Cov.: 32

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

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.: 32 Cov.: 31 AF XY: 0.000892 AC XY: 648 AN XY: 726786

African (AFR) AF: 0.0377 AC: 1260 AN: 33444

American (AMR) AF: 0.00197 AC: 88 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111408

Other (OTH) AF: 0.00181 AC: 109 AN: 60362

GnomAD4 genome AF: 0.0105 AC: 1595 AN: 152126 Hom.: 24 Cov.: 32 AF XY: 0.00995 AC XY: 740 AN XY: 74370

African (AFR) AF: 0.0364 AC: 1512 AN: 41506

American (AMR) AF: 0.00432 AC: 66 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67978

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00176 Hom.: 3

Bravo AF: 0.0117

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00347 AC: 421

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.6
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.095
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.23
MVP		0.15
MPC		0.028
ClinPred		0.073	T
GERP RS		-1.3
Varity_R		0.42
gMVP		0.17
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs16924241; hg19: chr9-6256144;