rs4252041

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• sterile multifocal osteomyelitis with periostitis and pustulosis

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 330833.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173842.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RN	NM_173842.3	MANE Select	c.*162C>T		3_prime_UTR	Exon 4 of 4	NP_776214.1	P18510-1
	IL1RN	NM_173841.3		c.*162C>T		3_prime_UTR	Exon 6 of 6	NP_776213.1	P18510-3
	IL1RN	NM_000577.5		c.*162C>T		3_prime_UTR	Exon 5 of 5	NP_000568.1	P18510-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RN	ENST00000409930.4	TSL:1 MANE Select	c.*162C>T		3_prime_UTR	Exon 4 of 4	ENSP00000387173.3	P18510-1
	IL1RN	ENST00000259206.9	TSL:1	c.*162C>T		3_prime_UTR	Exon 6 of 6	ENSP00000259206.5	P18510-3
	IL1RN	ENST00000354115.6	TSL:1	c.*162C>T		3_prime_UTR	Exon 5 of 5	ENSP00000329072.3	P18510-2

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

African (AFR) AF: 0.00814 AC: 127 AN: 15594

American (AMR) AF: 0.0224 AC: 746 AN: 33260

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 459 AN: 18758

East Asian (EAS) AF: 0.00 AC: 0 AN: 31980

South Asian (SAS) AF: 0.0361 AC: 2200 AN: 60988

European-Finnish (FIN) AF: 0.0193 AC: 735 AN: 38034

Middle Eastern (MID) AF: 0.0658 AC: 160 AN: 2432

European-Non Finnish (NFE) AF: 0.0430 AC: 13975 AN: 325050

Other (OTH) AF: 0.0364 AC: 1099 AN: 30218

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

African (AFR) AF: 0.00762 AC: 317 AN: 41582

American (AMR) AF: 0.0337 AC: 515 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 88 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0304 AC: 147 AN: 4830

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10628

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0413 AC: 2810 AN: 68032

Other (OTH) AF: 0.0303 AC: 64 AN: 2114

Alfa AF: 0.0359 Hom.: 268

Bravo AF: 0.0273

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Autoinflammatory syndrome (1)
-	-	1	not provided (1)
-	-	1	Sterile multifocal osteomyelitis with periostitis and pustulosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.9
DANN	Benign	0.93
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs4252041; hg19: chr2-113890610;