rs4252041

Variant names:

• chr2-113133033-C-T
• rs4252041
• NM_173842.3:c.*162C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_173842.3(IL1RN):​c.*162C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 708,662 control chromosomes in the GnomAD database, including 534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.027 (89 hom., cov: 32)
  • Exomes 𝑓: 0.035 (445 hom.)
• Consequence: IL1RN NM_173842.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.534

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 (BayesDel_noAF=-0.48).
• BP6: Variant 2-113133033-C-T is Benign according to our data. Variant chr2-113133033-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330833.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr2-113133033-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL1RN	NM_173842.3	c.*162C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000409930.4	NP_776214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL1RN	ENST00000409930.4	c.*162C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_173842.3	ENSP00000387173.3

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4093 AN: 152230 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0338

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0301

GnomAD4 exome AF: 0.0351 AC: 19501 AN: 556314 Hom.: 445 Cov.: 6 AF XY: 0.0359 AC XY: 10755 AN XY: 299612

Gnomad4 AFR exome AF: 0.00814

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0361

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.0430

Gnomad4 OTH exome AF: 0.0364

GnomAD4 genome AF: 0.0269 AC: 4092 AN: 152348 Hom.: 89 Cov.: 32 AF XY: 0.0252 AC XY: 1881 AN XY: 74506

Gnomad4 AFR AF: 0.00762

Gnomad4 AMR AF: 0.0337

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0304

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0413

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0381 Hom.: 92

Bravo AF: 0.0273

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autoinflammatory syndrome Uncertain:1

Jan 10, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sterile multifocal osteomyelitis with periostitis and pustulosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.9
DANN	Benign	0.93

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: rs4252041; hg19: chr2-113890610;