9-6253553-T-A

Variant names:

• chr9-6253553-T-A
• rs763716717
• NM_033439.4:c.471T>A

Variant summary

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

The NM_033439.4(IL33):​c.471T>A​(p.Asp157Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,449,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: IL33 NM_033439.4 missense, splice_region
• Scores: Splicing: ADA: 0.0009054
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.505

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=0.23763698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL33	NM_033439.4	c.471T>A	p.Asp157Glu	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000682010.1	NP_254274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL33	ENST00000682010.1	c.471T>A	p.Asp157Glu	missense_variant, splice_region_variant	Exon 6 of 8		NM_033439.4	ENSP00000507310.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000601

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1449816 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 721220

Gnomad4 AFR exome AF: 0.0000603

Gnomad4 AMR exome AF: 0.0000459

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.471T>A (p.D157E) alteration is located in exon 6 (coding exon 5) of the IL33 gene. This alteration results from a T to A substitution at nucleotide position 471, causing the aspartic acid (D) at amino acid position 157 to be replaced by a glutamic acid (E). 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	Benign	0.27
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.35	.;T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.4	.;D;D
REVEL	Benign	0.052
Sift	Benign	0.080	.;T;T
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.13	.;B;.
Vest4		0.29
MutPred		0.23		.;Gain of helix (P = 0.062);.;
MVP		0.48
MPC		0.031
ClinPred		0.22	T
GERP RS		-2.5
Varity_R		0.22
gMVP		0.097

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00091
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.11		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: rs763716717; hg19: chr9-6253553;