rs45507693

Positions:

chr2-113132707-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_173842.3(IL1RN):c.370G>A(p.Ala124Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,232 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 18 hom. )

Consequence

IL1RN
NM_173842.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.103

Variant links:

Genes affected

IL1RN (HGNC:6000): (interleukin 1 receptor antagonist) The protein encoded by this gene is a member of the interleukin 1 cytokine family. This protein inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 1 related immune and inflammatory responses, particularly in the acute phase of infection and inflammation. This gene and five other closely related cytokine genes form a gene cluster spanning approximately 400 kb on chromosome 2. A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures and gastric cancer. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Aug 2020]

IL1RN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008407414).

BP6

Variant 2-113132707-G-A is Benign according to our data. Variant chr2-113132707-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 470170.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr2-113132707-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00127 (193/152340) while in subpopulation EAS AF= 0.0106 (55/5178). AF 95% confidence interval is 0.00838. There are 1 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL1RN	NM_173842.3 linkuse as main transcript	c.370G>A	p.Ala124Thr	missense_variant	4/4	ENST00000409930.4	NP_776214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL1RN	ENST00000409930.4 linkuse as main transcript	c.370G>A	p.Ala124Thr	missense_variant	4/4	1	NM_173842.3	ENSP00000387173	P4	P18510-1

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.0110

Gnomad SAS

AF:

0.00661

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00313

AC:

786

AN:

251316

Hom.:

AF XY:

0.00330

AC XY:

448

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.0159

Gnomad SAS exome

AF:

0.00973

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000731

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00137

AC:

1997

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1141

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00474

Gnomad4 EAS exome

AF:

0.0107

Gnomad4 SAS exome

AF:

0.00815

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000385

Gnomad4 OTH exome

AF:

0.00303

GnomAD4 genome

AF:

0.00127

AC:

193

AN:

152340

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000793

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.0106

Gnomad4 SAS

AF:

0.00662

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00176

Hom.:

Bravo

AF:

0.00167

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00300

AC:

364

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	IL1RN: BP4, BS1, BS2 -

Sterile multifocal osteomyelitis with periostitis and pustulosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 09, 2022

- -

IL1RN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.36

DANN

Benign

0.60

DEOGEN2

Benign

0.13

.;.;.;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.16

.;T;T;T;T

MetaRNN

Benign

0.0084

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.6

.;.;.;.;N

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

2.5

N;N;N;N;N

REVEL

Benign

0.029

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0020, 0.011

.;.;.;B;B

Vest4

0.050

MVP

0.24

MPC

0.053

ClinPred

0.000019

GERP RS

-0.80

Varity_R

0.076

gMVP

0.56

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

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