2-112779528-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000575.5(IL1A):c.458C>T(p.Thr153Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000442 in 1,606,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T153T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: IL1A NM_000575.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.93

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022092432).
• BP6: Variant 2-112779528-G-A is Benign according to our data. Variant chr2-112779528-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2367676.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1A	NM_000575.5	c.458C>T	p.Thr153Met	missense_variant	5/7	ENST00000263339.4
IL1A	NM_001371554.1	c.458C>T	p.Thr153Met	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1A	ENST00000263339.4	c.458C>T	p.Thr153Met	missense_variant	5/7	1	NM_000575.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000837 AC: 21 AN: 250848 Hom.: 0 AF XY: 0.0000959 AC XY: 13 AN XY: 135572

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000454 AC: 66 AN: 1453670 Hom.: 0 Cov.: 30 AF XY: 0.0000540 AC XY: 39 AN XY: 722652

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000244

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74482

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.0040
Dann	Benign	0.65
DEOGEN2	Benign	0.088	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.023
Sift	Benign	0.30	T
Sift4G	Benign	0.16	T
Polyphen		0.014	B
Vest4		0.030
MVP		0.095
MPC		0.25
ClinPred		0.014	T
GERP RS		-9.3
Varity_R		0.036
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376874217; hg19: chr2-113537105;