chr9-6251218-C-T

Variant names:

• chr9-6251218-C-T
• NM_033439.4:c.296C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033439.4(IL33):​c.296C>T​(p.Ser99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 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: 0.0000014 (0 hom.)
• Consequence: IL33 NM_033439.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.338
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.296C>T	p.Ser99Leu	missense	Exon 4 of 8	NP_254274.1	O95760-1
	IL33	NM_001314044.2		c.296C>T	p.Ser99Leu	missense	Exon 4 of 8	NP_001300973.1	O95760-1
	IL33	NM_001314045.2		c.296C>T	p.Ser99Leu	missense	Exon 4 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.296C>T	p.Ser99Leu	missense	Exon 4 of 8	ENSP00000507310.1	O95760-1
	IL33	ENST00000381434.7	TSL:1	c.296C>T	p.Ser99Leu	missense	Exon 3 of 7	ENSP00000370842.3	O95760-1
	IL33	ENST00000611532.4	TSL:1	c.217+619C>T		intron	N/A	ENSP00000478858.1	O95760-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461638 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111834

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.5
DANN	Benign	0.96
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.34
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.11
Sift	Benign	0.097	T
Sift4G	Benign	0.34	T
Polyphen		0.0070	B
Vest4		0.27
MutPred		0.34		Loss of glycosylation at S99 (P = 0.0172)
MVP		0.26
MPC		0.0079
ClinPred		0.16	T
GERP RS		0.17
Varity_R		0.048
gMVP		0.036
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 47

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr9-6251218;