2-112917677-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_014439.4(IL37):c.308C>T(p.Ala103Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000802 in 1,608,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: IL37 NM_014439.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.442

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02517429).
• BP6: Variant 2-112917677-C-T is Benign according to our data. Variant chr2-112917677-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2354250.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL37	NM_014439.4	c.308C>T	p.Ala103Val	missense_variant	5/6	ENST00000263326.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL37	ENST00000263326.8	c.308C>T	p.Ala103Val	missense_variant	5/6	1	NM_014439.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000101 AC: 25 AN: 246998 Hom.: 0 AF XY: 0.000105 AC XY: 14 AN XY: 133428

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00145

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.0000674

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000844 AC: 123 AN: 1456742 Hom.: 0 Cov.: 31 AF XY: 0.0000856 AC XY: 62 AN XY: 724564

Gnomad4 AFR exome AF: 0.0000603

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00171

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000352

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000577

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.308C>T (p.A103V) alteration is located in exon 4 (coding exon 4) of the IL37 gene. This alteration results from a C to T substitution at nucleotide position 308, causing the alanine (A) at amino acid position 103 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

IL37: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.64
Dann	Benign	0.76
DEOGEN2	Benign	0.0016	T;.;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.53	T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.025	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.37	N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.29	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.13	B;B;B;B;B
Vest4		0.040
MVP		0.072
MPC		0.089
ClinPred		0.012	T
GERP RS		-5.8
Varity_R		0.11
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs765216544; hg19: chr2-113675254;