2-112917210-A-C

Variant names:

• chr2-112917210-A-C
• rs1224546521
• NM_014439.4:c.227A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014439.4(IL37):​c.227A>C​(p.Asn76Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. N76S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IL37 NM_014439.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.66
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055833995).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL37	NM_014439.4	MANE Select	c.227A>C	p.Asn76Thr	missense	Exon 4 of 6	NP_055254.2
	IL37	NM_173202.2		c.164A>C	p.Asn55Thr	missense	Exon 3 of 5	NP_775294.1	Q9NZH6-4
	IL37	NM_173205.2		c.149A>C	p.Asn50Thr	missense	Exon 2 of 4	NP_775297.1	Q9NZH6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL37	ENST00000263326.8	TSL:1 MANE Select	c.227A>C	p.Asn76Thr	missense	Exon 4 of 6	ENSP00000263326.3	Q9NZH6-1
	IL37	ENST00000352179.7	TSL:1	c.164A>C	p.Asn55Thr	missense	Exon 2 of 4	ENSP00000263327.3	Q9NZH6-4
	IL37	ENST00000311328.2	TSL:1	c.149A>C	p.Asn50Thr	missense	Exon 2 of 4	ENSP00000309883.2	Q9NZH6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251244 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461764 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111936

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0060
DANN	Benign	0.098
DEOGEN2	Benign	0.00047	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-4.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.057
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.077
MutPred		0.52		Loss of catalytic residue at N76 (P = 0.1718)
MVP		0.12
MPC		0.087
ClinPred		0.038	T
GERP RS		-5.0
Varity_R		0.063
gMVP		0.060
Mutation Taster		=83/17	polymorphism

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: rs1224546521; hg19: chr2-113674787;