3-190604401-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002182.4(IL1RAP):c.338C>A(p.Thr113Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IL1RAP NM_002182.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76

Genes affected

IL1RAP (HGNC:5995): (interleukin 1 receptor accessory protein) This gene encodes a component of the interleukin 1 receptor complex, which initiates signalling events that result in the activation of interleukin 1-responsive genes. Alternative splicing of this gene results in membrane-bound and soluble isoforms differing in their C-terminus. The ratio of soluble to membrane-bound forms increases during acute-phase induction or stress. [provided by RefSeq, Jul 2018]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1RAP	NM_002182.4	c.338C>A	p.Thr113Asn	missense_variant	4/12	ENST00000447382.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RAP	ENST00000447382.6	c.338C>A	p.Thr113Asn	missense_variant	4/12	1	NM_002182.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250310 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.338C>A (p.T113N) alteration is located in exon 4 (coding exon 2) of the IL1RAP gene. This alteration results from a C to A substitution at nucleotide position 338, causing the threonine (T) at amino acid position 113 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D;D;T;.;.;.;T;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.2	M;M;M;.;M;M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;N;D;D;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D;D;.;D;D
Vest4		0.62
MutPred		0.56		Gain of catalytic residue at T113 (P = 0.1538);Gain of catalytic residue at T113 (P = 0.1538);Gain of catalytic residue at T113 (P = 0.1538);Gain of catalytic residue at T113 (P = 0.1538);Gain of catalytic residue at T113 (P = 0.1538);Gain of catalytic residue at T113 (P = 0.1538);Gain of catalytic residue at T113 (P = 0.1538);Gain of catalytic residue at T113 (P = 0.1538);Gain of catalytic residue at T113 (P = 0.1538);Gain of catalytic residue at T113 (P = 0.1538);
MVP		0.72
MPC		1.0
ClinPred		0.95	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs777978848; hg19: chr3-190322190;