2-112779589-C-T

Variant names:

• chr2-112779589-C-T
• rs553259442
• NM_000575.5:c.397G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000575.5(IL1A):​c.397G>A​(p.Glu133Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,612,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E133Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: IL1A NM_000575.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.311
• Publications: 1 publications found

Genes affected

IL1A (HGNC:5991): (interleukin 1 alpha) The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine is a pleiotropic cytokine involved in various immune responses, inflammatory processes, and hematopoiesis. This cytokine is produced by monocytes and macrophages as a proprotein, which is proteolytically processed and released in response to cell injury, and thus induces apoptosis. This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. It has been suggested that the polymorphism of these genes is associated with rheumatoid arthritis and Alzheimer's disease. [provided by RefSeq, Jul 2008]

ENSG00000299339 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053578973).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000575.5. 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
	IL1A	NM_000575.5	MANE Select	c.397G>A	p.Glu133Lys	missense	Exon 5 of 7	NP_000566.3
	IL1A	NM_001371554.1		c.397G>A	p.Glu133Lys	missense	Exon 5 of 7	NP_001358483.1	P01583

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1A	ENST00000263339.4	TSL:1 MANE Select	c.397G>A	p.Glu133Lys	missense	Exon 5 of 7	ENSP00000263339.3	P01583
	IL1A	ENST00000959423.1		c.397G>A	p.Glu133Lys	missense	Exon 4 of 6	ENSP00000629482.1
	ENSG00000299339	ENST00000762706.1		n.404+8693C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251354 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1460436 Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25 AN XY: 726556

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.0000671 AC: 3 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1110854

Other (OTH) AF: 0.0000663 AC: 4 AN: 60332

GnomAD4 genome AF: 0.000132 AC: 20 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74252

African (AFR) AF: 0.0000242 AC: 1 AN: 41396

American (AMR) AF: 0.000917 AC: 14 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.000959 AC: 2 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000227

ExAC AF: 0.000140 AC: 17

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.5
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.31
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.027
Sift	Benign	0.18	T
Sift4G	Benign	0.24	T
Polyphen		0.042	B
Vest4		0.11
MutPred		0.48		Gain of MoRF binding (P = 0.0037)
MVP		0.28
MPC		0.27
ClinPred		0.028	T
GERP RS		-0.77
Varity_R		0.079
gMVP		0.20
Mutation Taster		=94/6	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: rs553259442; hg19: chr2-113537166; COSMIC: COSV54520084;