Genetic Variant IL1RN:p.Ala124Pro (chr2-113132707-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173842.3(IL1RN):c.370G>C(p.Ala124Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A124T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IL1RN
NM_173842.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.103

Publications

0 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

IL1RN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL1RN	NM_173842.3 link	c.370G>C	p.Ala124Pro	missense_variant	Exon 4 of 4	ENST00000409930.4	NP_776214.1	P18510-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL1RN	ENST00000409930.4 link	c.370G>C	p.Ala124Pro	missense_variant	Exon 4 of 4	1	NM_173842.3	ENSP00000387173.3		P18510-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

.;.;.;.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.53

.;T;T;T;T

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.50

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;.;.;.;L

PhyloP100

-0.10

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.6

N;N;N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D

Polyphen

0.84, 0.99

.;.;.;P;D

Vest4

0.34

MutPred

0.78

.;.;.;.;Gain of disorder (P = 0.0359);

MVP

0.32

MPC

0.36

ClinPred

0.89

GERP RS

-0.80

Varity_R

0.91

gMVP

0.86

Mutation Taster

=90/10

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over