3-190604334-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002182.4(IL1RAP):c.271C>T(p.Arg91Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 1.39

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL1RAP	NM_002182.4	c.271C>T	p.Arg91Cys	missense_variant	4/12	ENST00000447382.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL1RAP	ENST00000447382.6	c.271C>T	p.Arg91Cys	missense_variant	4/12	1	NM_002182.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jul 20, 2022

The c.271C>T (p.R91C) alteration is located in exon 4 (coding exon 2) of the IL1RAP gene. This alteration results from a C to T substitution at nucleotide position 271, causing the arginine (R) at amino acid position 91 to be replaced by a cysteine (C). 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	0.89
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D;D;T;.;.;.;D;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.0	M;M;M;.;M;M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D;D;.;D;D
Vest4		0.51
MutPred		0.70		Loss of disorder (P = 0.0118);Loss of disorder (P = 0.0118);Loss of disorder (P = 0.0118);Loss of disorder (P = 0.0118);Loss of disorder (P = 0.0118);Loss of disorder (P = 0.0118);Loss of disorder (P = 0.0118);Loss of disorder (P = 0.0118);Loss of disorder (P = 0.0118);Loss of disorder (P = 0.0118);
MVP		0.94
MPC		2.7
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-190322123;