9-6254477-G-C

Position:

• chr9-6254477-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033439.4(IL33):​c.536G>C​(p.Gly179Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,435,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: IL33 NM_033439.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

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]

LOC107987046 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1396333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL33	NM_033439.4	c.536G>C	p.Gly179Ala	missense_variant	7/8	ENST00000682010.1	NP_254274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL33	ENST00000682010.1	c.536G>C	p.Gly179Ala	missense_variant	7/8		NM_033439.4	ENSP00000507310.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435974 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 713934

Gnomad4 AFR exome AF: 0.0000303

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2024

The c.536G>C (p.G179A) alteration is located in exon 7 (coding exon 6) of the IL33 gene. This alteration results from a G to C substitution at nucleotide position 536, causing the glycine (G) at amino acid position 179 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	.;.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.042	N
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;.;L;.
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.5	D;.;D;D
REVEL	Benign	0.053
Sift	Uncertain	0.011	D;.;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.88	.;.;P;.
Vest4		0.21
MutPred		0.36		.;.;Gain of catalytic residue at M183 (P = 0.043);.;
MVP		0.47
MPC		0.020
ClinPred		0.72	D
GERP RS		2.0
Varity_R		0.28
gMVP		0.099

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

LitVar

Other links and lift over

dbSNP: rs768931199; hg19: chr9-6254477;