Genetic Variant NM_003855.5:c.753C>A (chr2-102384942-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003855.5(IL18R1):c.753C>A(p.Phe251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IL18R1
NM_003855.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.326

Publications

50 publications found

Variant links:

Genes affected

IL18R1 (HGNC:5988): (interleukin 18 receptor 1) The protein encoded by this gene is a cytokine receptor that belongs to the interleukin 1 receptor family. This receptor specifically binds interleukin 18 (IL18), and is essential for IL18 mediated signal transduction. IFN-alpha and IL12 are reported to induce the expression of this receptor in NK and T cells. This gene along with four other members of the interleukin 1 receptor family, including IL1R2, IL1R1, ILRL2 (IL-1Rrp2), and IL1RL1 (T1/ST2), form a gene cluster on chromosome 2q. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

IL18R1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07130396).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003855.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL18R1	NM_003855.5	MANE Select	c.753C>A	p.Phe251Leu	missense	Exon 7 of 11	NP_003846.1	Q13478
IL18R1	NM_001371418.1		c.753C>A	p.Phe251Leu	missense	Exon 7 of 11	NP_001358347.1	B7ZKV7
IL18R1	NM_001371419.1		c.753C>A	p.Phe251Leu	missense	Exon 7 of 9	NP_001358348.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL18R1	ENST00000233957.7	TSL:5 MANE Select	c.753C>A	p.Phe251Leu	missense	Exon 7 of 11	ENSP00000233957.1	Q13478
IL18R1	ENST00000409599.5	TSL:5	c.753C>A	p.Phe251Leu	missense	Exon 8 of 12	ENSP00000387211.1	Q13478
IL18R1	ENST00000410040.5	TSL:2	c.753C>A	p.Phe251Leu	missense	Exon 7 of 11	ENSP00000386663.1	Q13478

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455106

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724216

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33368

American (AMR)

AF:

0.00

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39500

South Asian (SAS)

AF:

0.00

AC:

AN:

85846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106442

Other (OTH)

AF:

0.00

AC:

AN:

60170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

8.5

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.13

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.36

M_CAP

Benign

0.0036

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

PhyloP100

0.33

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.85

REVEL

Benign

0.0080

Sift

Benign

0.25

Sift4G

Benign

0.61

Polyphen

0.0020

Vest4

0.059

MutPred

0.43

Loss of sheet (P = 0.1501)

MVP

0.092

MPC

0.23

ClinPred

0.037

GERP RS

-0.95

Varity_R

0.15

gMVP

0.68

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over