rs16924241

Positions:

• chr9-6256144-C-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL33	NM_033439.4	c.789C>G	p.Ile263Met	missense_variant	8/8	ENST00000682010.1	NP_254274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL33	ENST00000682010.1	c.789C>G	p.Ile263Met	missense_variant	8/8		NM_033439.4	ENSP00000507310.1

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

GnomAD3 exomes AF: 0.00272 AC: 683 AN: 250884 Hom.: 16 AF XY: 0.00173 AC XY: 235 AN XY: 135590

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0377

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00181

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

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00473

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;L;.
PrimateAI	Benign	0.40	T
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	T
GERP RS		-1.3
Varity_R		0.42
gMVP		0.17

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: rs16924241; hg19: chr9-6256144;