rs45507693

chr2-113132707-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.103

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]

ACMG classification

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=5, 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1RN	NM_173842.3	c.370G>A	p.Ala124Thr	missense_variant	4/4	ENST00000409930.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RN	ENST00000409930.4	c.370G>A	p.Ala124Thr	missense_variant	4/4	1	NM_173842.3	P4

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152222 Hom.: 1 Cov.: 33

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.: 6 AF XY: 0.00330 AC XY: 448 AN XY: 135832

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.: 18 Cov.: 31 AF XY: 0.00157 AC XY: 1141 AN XY: 727246

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.: 1 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74496

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.: 5

Bravo AF: 0.00167

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00300 AC: 364

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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	Invitae	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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.36
Dann	Benign	0.60
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.015	N
MetaRNN	Benign	0.0084	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs45507693; hg19: chr2-113890284; COSMIC: COSV52080428; COSMIC: COSV52080428;