dbSNP rs45507693: IL1RN:p.Ala124Thr (chr2-113132707-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

18 publications found

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 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

IL1RN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 470170.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 18 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL1RN	NM_173842.3	MANE Select	c.370G>A	p.Ala124Thr	missense	Exon 4 of 4	NP_776214.1	P18510-1
IL1RN	NM_173841.3		c.379G>A	p.Ala127Thr	missense	Exon 6 of 6	NP_776213.1	P18510-3
IL1RN	NM_000577.5		c.316G>A	p.Ala106Thr	missense	Exon 5 of 5	NP_000568.1	P18510-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL1RN	ENST00000409930.4	TSL:1 MANE Select	c.370G>A	p.Ala124Thr	missense	Exon 4 of 4	ENSP00000387173.3	P18510-1
IL1RN	ENST00000259206.9	TSL:1	c.379G>A	p.Ala127Thr	missense	Exon 6 of 6	ENSP00000259206.5	P18510-3
IL1RN	ENST00000354115.6	TSL:1	c.316G>A	p.Ala106Thr	missense	Exon 5 of 5	ENSP00000329072.3	P18510-2

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

GnomAD2 exomes

AF:

0.00313

AC:

786

AN:

251316

AF XY:

0.00330

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 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

African (AFR)

AF:

0.000926

AC:

AN:

33480

American (AMR)

AF:

0.000738

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00474

AC:

124

AN:

26136

East Asian (EAS)

AF:

0.0107

AC:

424

AN:

39700

South Asian (SAS)

AF:

0.00815

AC:

703

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000385

AC:

428

AN:

1112010

Other (OTH)

AF:

0.00303

AC:

183

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

142

285

427

570

712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00127

AC:

193

AN:

152340

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000793

AC:

AN:

41588

American (AMR)

AF:

0.000981

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.0106

AC:

AN:

5178

South Asian (SAS)

AF:

0.00662

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00159

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Sterile multifocal osteomyelitis with periostitis and pustulosis (2)

Autoinflammatory syndrome (1)

IL1RN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.36

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.13

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0084

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.6

PhyloP100

-0.10

PrimateAI

Benign

0.29

PROVEAN

Benign

2.5

REVEL

Benign

0.029

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.050

MVP

0.24

MPC

0.053

ClinPred

0.000019

GERP RS

-0.80

Varity_R

0.076

gMVP

0.56

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over