11-72000353-C-T

Position:

chr11-72000353-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001039660.2(IL18BP):c.31C>T(p.Leu11Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

IL18BP
NM_001039660.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.07

Variant links:

Genes affected

IL18BP (HGNC:5987): (interleukin 18 binding protein) The protein encoded by this gene functions as an inhibitor of the proinflammatory cytokine, IL18. It binds IL18, prevents the binding of IL18 to its receptor, and thus inhibits IL18-induced IFN-gamma production, resulting in reduced T-helper type 1 immune responses. This protein is constitutively expressed and secreted in mononuclear cells. Elevated level of this protein is detected in the intestinal tissues of patients with Crohn's disease. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2011]

IL18BP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040527344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL18BP	NM_001039660.2 linkuse as main transcript	c.31C>T	p.Leu11Phe	missense_variant, splice_region_variant	3/6	ENST00000393703.9	NP_001034749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL18BP	ENST00000393703.9 linkuse as main transcript	c.31C>T	p.Leu11Phe	missense_variant, splice_region_variant	3/6	3	NM_001039660.2	ENSP00000377306	P1	O95998-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000322

AC:

AN:

248330

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000445

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:

0.00000547

AC:

AN:

1461368

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

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

AF:

0.0000197

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.31C>T (p.L11F) alteration is located in exon 2 (coding exon 2) of the IL18BP gene. This alteration results from a C to T substitution at nucleotide position 31, causing the leucine (L) at amino acid position 11 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 13, 2022

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 11 of the IL18BP protein (p.Leu11Phe). This variant is present in population databases (rs768254158, gnomAD 0.05%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with IL18BP-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.88

DANN

Benign

0.91

DEOGEN2

Benign

0.016

T;T;T;T;.;T;T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.66

.;.;.;.;T;T;.;T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.041

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.;N;N;N;.;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.71

N;N;N;N;.;N;N;N;N

REVEL

Benign

0.012

Sift

Benign

0.47

T;T;T;T;.;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;.;B;B;B;B

Vest4

0.11

MutPred

0.39

Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);Gain of solvent accessibility (P = 0.0281);

MVP

0.26

MPC

0.046

ClinPred

0.020

GERP RS

-3.0

Varity_R

0.036

gMVP

0.084

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over