Genetic Variant NM_016232.5:c.526G>A (chr2-102340744-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016232.5(IL1RL1):c.526G>A(p.Ala176Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,597,556 control chromosomes in the GnomAD database, including 21 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 18 hom. )

Consequence

IL1RL1
NM_016232.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.21

Publications

8 publications found

Variant links:

Genes affected

IL1RL1 (HGNC:5998): (interleukin 1 receptor like 1) The protein encoded by this gene is a member of the interleukin 1 receptor family. Studies of the similar gene in mouse suggested that this receptor can be induced by proinflammatory stimuli, and may be involved in the function of helper T cells. This gene, interleukin 1 receptor, type I (IL1R1), interleukin 1 receptor, type II (IL1R2) and interleukin 1 receptor-like 2 (IL1RL2) form a cytokine receptor gene cluster in a region mapped to chromosome 2q12. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

IL1RL1 links:

IL18R1 (HGNC:5988): (interleukin 18 receptor 1) The protein encoded by this gene is a cytokine receptor that belongs to the interleukin 1 receptor family. This receptor specifically binds interleukin 18 (IL18), and is essential for IL18 mediated signal transduction. IFN-alpha and IL12 are reported to induce the expression of this receptor in NK and T cells. This gene along with four other members of the interleukin 1 receptor family, including IL1R2, IL1R1, ILRL2 (IL-1Rrp2), and IL1RL1 (T1/ST2), form a gene cluster on chromosome 2q. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

IL18R1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069009066).

BP6

Variant 2-102340744-G-A is Benign according to our data. Variant chr2-102340744-G-A is described in ClinVar as Benign. ClinVar VariationId is 1629553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00307 (468/152338) while in subpopulation EAS AF = 0.0322 (167/5192). AF 95% confidence interval is 0.0282. There are 3 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016232.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL1RL1	NM_016232.5	MANE Select	c.526G>A	p.Ala176Thr	missense	Exon 5 of 11	NP_057316.3
IL1RL1	NM_003856.4		c.526G>A	p.Ala176Thr	missense	Exon 5 of 8	NP_003847.2
IL1RL1	NM_001282408.2		c.175G>A	p.Ala59Thr	missense	Exon 4 of 7	NP_001269337.1	Q01638-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL1RL1	ENST00000233954.6	TSL:1 MANE Select	c.526G>A	p.Ala176Thr	missense	Exon 5 of 11	ENSP00000233954.1	Q01638-1
IL1RL1	ENST00000311734.6	TSL:1	c.526G>A	p.Ala176Thr	missense	Exon 5 of 8	ENSP00000310371.2	Q01638-2
IL1RL1	ENST00000427077.1	TSL:1	n.526G>A		non_coding_transcript_exon	Exon 5 of 9	ENSP00000391120.1	Q01638-3

Frequencies

GnomAD3 genomes

AF:

0.00307

AC:

468

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0321

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00170

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00420

AC:

987

AN:

234962

AF XY:

0.00395

show subpopulations

Gnomad AFR exome

AF:

0.00145

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.0294

Gnomad FIN exome

AF:

0.000419

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00423

GnomAD4 exome

AF:

0.00248

AC:

3579

AN:

1445218

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

1775

AN XY:

719232

show subpopulations

African (AFR)

AF:

0.00264

AC:

AN:

32198

American (AMR)

AF:

0.00112

AC:

AN:

40282

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

290

AN:

25704

East Asian (EAS)

AF:

0.0265

AC:

1022

AN:

38526

South Asian (SAS)

AF:

0.00259

AC:

217

AN:

83804

European-Finnish (FIN)

AF:

0.000450

AC:

AN:

53330

Middle Eastern (MID)

AF:

0.00996

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00146

AC:

1617

AN:

1105968

Other (OTH)

AF:

0.00372

AC:

222

AN:

59684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

172

344

516

688

860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00307

AC:

468

AN:

152338

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

233

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41578

American (AMR)

AF:

0.00222

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.0322

AC:

167

AN:

5192

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00171

AC:

116

AN:

68034

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

108

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:

0.00333

Hom.:

Bravo

AF:

0.00385

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00463

AC:

562

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.27

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.061

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.080

PhyloP100

-1.2

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.30

REVEL

Benign

0.052

Sift

Benign

0.28

Sift4G

Benign

0.86

Polyphen

0.14

Vest4

0.082

MVP

0.19

MPC

0.011

ClinPred

0.0019

GERP RS

-4.0

Varity_R

0.11

gMVP

0.44

Mutation Taster

=100/0

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