2-112913833-A-G

Position:

• chr2-112913833-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014439.4(IL37):​c.124A>G​(p.Thr42Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,611,040 control chromosomes in the GnomAD database, including 395,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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 0.61 (30741 hom., cov: 31)
  • Exomes 𝑓: 0.70 (364433 hom.)
• Consequence: IL37 NM_014439.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.681

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4006786E-6).
• BP6: Variant 2-112913833-A-G is Benign according to our data. Variant chr2-112913833-A-G is described in ClinVar as [Benign]. Clinvar id is 767816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL37	NM_014439.4	c.124A>G	p.Thr42Ala	missense_variant	3/6	ENST00000263326.8	NP_055254.2
IL37	NM_173204.2	c.124A>G	p.Thr42Ala	missense_variant	3/5		NP_775296.1
IL37	NM_173202.2	c.82+739A>G		intron_variant			NP_775294.1
IL37	NM_173203.2	c.82+739A>G		intron_variant			NP_775295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL37	ENST00000263326.8	c.124A>G	p.Thr42Ala	missense_variant	3/6	1	NM_014439.4	ENSP00000263326	P1
IL37	ENST00000353225.7	c.124A>G	p.Thr42Ala	missense_variant	2/4	1		ENSP00000309208
IL37	ENST00000349806.7	c.82+739A>G		intron_variant		1		ENSP00000263328
IL37	ENST00000352179.7	c.82+739A>G		intron_variant		1		ENSP00000263327

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92524 AN: 151800 Hom.: 30720 Cov.: 31

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.690

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.639

GnomAD3 exomes AF: 0.711 AC: 177949 AN: 250348 Hom.: 65289 AF XY: 0.714 AC XY: 96566 AN XY: 135320

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.843

Gnomad ASJ exome AF: 0.729

Gnomad EAS exome AF: 0.827

Gnomad SAS exome AF: 0.730

Gnomad FIN exome AF: 0.728

Gnomad NFE exome AF: 0.699

Gnomad OTH exome AF: 0.713

GnomAD4 exome AF: 0.703 AC: 1025118 AN: 1459124 Hom.: 364433 Cov.: 45 AF XY: 0.703 AC XY: 510676 AN XY: 725934

Gnomad4 AFR exome AF: 0.302

Gnomad4 AMR exome AF: 0.833

Gnomad4 ASJ exome AF: 0.728

Gnomad4 EAS exome AF: 0.814

Gnomad4 SAS exome AF: 0.732

Gnomad4 FIN exome AF: 0.719

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.696

GnomAD4 genome AF: 0.609 AC: 92581 AN: 151916 Hom.: 30741 Cov.: 31 AF XY: 0.617 AC XY: 45758 AN XY: 74216

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.752

Gnomad4 ASJ AF: 0.718

Gnomad4 EAS AF: 0.822

Gnomad4 SAS AF: 0.726

Gnomad4 FIN AF: 0.724

Gnomad4 NFE AF: 0.703

Gnomad4 OTH AF: 0.640

Alfa AF: 0.691 Hom.: 91018

Bravo AF: 0.600

TwinsUK AF: 0.714 AC: 2646

ALSPAC AF: 0.700 AC: 2698

ESP6500AA AF: 0.321 AC: 1415

ESP6500EA AF: 0.701 AC: 6032

ExAC AF: 0.694 AC: 84227

Asia WGS AF: 0.739 AC: 2569 AN: 3478

EpiCase AF: 0.704

EpiControl AF: 0.700

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 27775096) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.65
DANN	Benign	0.55
DEOGEN2	Benign	0.00024	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.17	T;T
MetaRNN	Benign	0.0000014	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.21	N;N
REVEL	Benign	0.053
Sift	Benign	0.53	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0	B;B
Vest4		0.019
MPC		0.084
ClinPred		0.00068	T
GERP RS		1.6
Varity_R		0.020
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs3811047; hg19: chr2-113671410; COSMIC: COSV54490369; COSMIC: COSV54490369;