rs444413

Variant names:

• chr2-113128249-G-A
• rs444413
• NM_173842.3:c.116+509G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173842.3(IL1RN):​c.116+509G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,202 control chromosomes in the GnomAD database, including 4,297 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4297 hom., cov: 32)
• Consequence: IL1RN NM_173842.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 6 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL1RN	NM_173842.3	c.116+509G>A		intron_variant	Intron 1 of 3	ENST00000409930.4	NP_776214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL1RN	ENST00000409930.4	c.116+509G>A		intron_variant	Intron 1 of 3	1	NM_173842.3	ENSP00000387173.3

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32898 AN: 152082 Hom.: 4289 Cov.: 32

Gnomad AFR AF: 0.0728

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0773

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.239

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.216 AC: 32935 AN: 152202 Hom.: 4297 Cov.: 32 AF XY: 0.219 AC XY: 16289 AN XY: 74398

African (AFR) AF: 0.0732 AC: 3041 AN: 41542

American (AMR) AF: 0.283 AC: 4334 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1011 AN: 3470

East Asian (EAS) AF: 0.0767 AC: 398 AN: 5188

South Asian (SAS) AF: 0.281 AC: 1358 AN: 4826

European-Finnish (FIN) AF: 0.306 AC: 3234 AN: 10568

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18763 AN: 67990

Other (OTH) AF: 0.241 AC: 509 AN: 2114

Alfa AF: 0.234 Hom.: 924

Bravo AF: 0.207

Asia WGS AF: 0.192 AC: 669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.56
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs444413; hg19: chr2-113885826; COSMIC: COSV52080015;