2-112918606-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (10 hom.)
• Consequence: IL37 NM_014439.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.04

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 767817.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL37	NM_014439.4	c.454C>T	p.Arg152Trp	missense_variant	6/6	ENST00000263326.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL37	ENST00000263326.8	c.454C>T	p.Arg152Trp	missense_variant	6/6	1	NM_014439.4	P1

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 839 AN: 152152 Hom.: 5 Cov.: 31

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

GnomAD3 exomes AF: 0.00174 AC: 436 AN: 251286 Hom.: 5 AF XY: 0.00126 AC XY: 171 AN XY: 135814

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 SAS exome AF: 0.0000653

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.: 10 Cov.: 31 AF XY: 0.000633 AC XY: 460 AN XY: 726814

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00290

Gnomad4 NFE exome AF: 0.0000800

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00550 AC: 838 AN: 152268 Hom.: 5 Cov.: 31 AF XY: 0.00531 AC XY: 395 AN XY: 74448

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00605

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Uncertain	0.86	D;D;D;D;D
MetaRNN	Benign	0.0056	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Benign	0.039
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.21
MVP		0.23
MPC		0.43
ClinPred		0.039	T
GERP RS		-2.1
Varity_R		0.30
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs28947200; hg19: chr2-113676183;