Genetic Variant NM_014439.4:c.454C>T (chr2-112918606-C-T) – 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_014439.4(IL37):c.454C>T(p.Arg152Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,613,374 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 5 hom., cov: 31)

Exomes 𝑓: 0.00073 ( 10 hom. )

Consequence

IL37
NM_014439.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.04

Publications

6 publications found

Variant links:

Genes affected

IL37 (HGNC:15563): (interleukin 37) The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine can bind to, and may be a ligand for interleukin 18 receptor (IL18R1/IL-1Rrp). This cytokine also binds to interleukin 18 binding protein (IL18BP), an inhibitory binding protein of interleukin 18 (IL18), and subsequently forms a complex with IL18 receptor beta subunit, and through which it inhibits the activity of IL18. This gene along with eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. Five alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

IL37 Gene-Disease associations (from GenCC):

inflammatory bowel disease (infantile ulcerative colitis) 31, autosomal recessive
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

IL37 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=0.005571276).

BP6

Variant 2-112918606-C-T is Benign according to our data. Variant chr2-112918606-C-T is described in ClinVar as Benign. ClinVar VariationId is 767817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0055 (838/152268) while in subpopulation AFR AF = 0.0177 (736/41548). AF 95% confidence interval is 0.0167. There are 5 homozygotes in GnomAd4. There are 395 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014439.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL37	NM_014439.4	MANE Select	c.454C>T	p.Arg152Trp	missense	Exon 6 of 6	NP_055254.2
IL37	NM_173202.2		c.391C>T	p.Arg131Trp	missense	Exon 5 of 5	NP_775294.1	Q9NZH6-4
IL37	NM_173205.2		c.376C>T	p.Arg126Trp	missense	Exon 4 of 4	NP_775297.1	Q9NZH6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL37	ENST00000263326.8	TSL:1 MANE Select	c.454C>T	p.Arg152Trp	missense	Exon 6 of 6	ENSP00000263326.3	Q9NZH6-1
IL37	ENST00000352179.7	TSL:1	c.391C>T	p.Arg131Trp	missense	Exon 4 of 4	ENSP00000263327.3	Q9NZH6-4
IL37	ENST00000311328.2	TSL:1	c.376C>T	p.Arg126Trp	missense	Exon 4 of 4	ENSP00000309883.2	Q9NZH6-2

Frequencies

GnomAD3 genomes

AF:

0.00551

AC:

839

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00174

AC:

436

AN:

251286

AF XY:

0.00126

show subpopulations

Gnomad AFR exome

AF:

0.0186

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00240

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000728

AC:

1064

AN:

1461106

Hom.:

Cov.:

AF XY:

0.000633

AC XY:

460

AN XY:

726814

show subpopulations

African (AFR)

AF:

0.0194

AC:

648

AN:

33448

American (AMR)

AF:

0.00127

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000479

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00290

AC:

155

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

0.0000800

AC:

AN:

1111892

Other (OTH)

AF:

0.00148

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00550

AC:

838

AN:

152268

Hom.:

Cov.:

AF XY:

0.00531

AC XY:

395

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0177

AC:

736

AN:

41548

American (AMR)

AF:

0.00255

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68020

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

122

162

203

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:

0.00219

Hom.:

Bravo

AF:

0.00605

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0186

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00194

AC:

236

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

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

0.14

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.0063

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0056

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

-1.0

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.039

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.21

MVP

0.23

MPC

0.43

ClinPred

0.039

GERP RS

-2.1

Varity_R

0.30

gMVP

0.32

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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