3-3070289-T-G

Position:

• chr3-3070289-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175726.4(IL5RA):​c.1199A>C​(p.Glu400Ala) 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 benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL5RA NM_175726.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

Genes affected

IL5RA (HGNC:6017): (interleukin 5 receptor subunit alpha) The protein encoded by this gene is an interleukin 5 specific subunit of a heterodimeric cytokine receptor. The receptor is comprised of a ligand specific alpha subunit and a signal transducing beta subunit shared by the receptors for interleukin 3 (IL3), colony stimulating factor 2 (CSF2/GM-CSF), and interleukin 5 (IL5). The binding of this protein to IL5 depends on the beta subunit. The beta subunit is activated by the ligand binding, and is required for the biological activities of IL5. This protein has been found to interact with syndecan binding protein (syntenin), which is required for IL5 mediated activation of the transcription factor SOX4. Several alternatively spliced transcript variants encoding four distinct isoforms have been reported. [provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17939422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL5RA	NM_175726.4	c.1199A>C	p.Glu400Ala	missense_variant	12/12	ENST00000446632.7	NP_783853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL5RA	ENST00000446632.7	c.1199A>C	p.Glu400Ala	missense_variant	12/12	5	NM_175726.4	ENSP00000412209.2
IL5RA	ENST00000256452.7	c.1199A>C	p.Glu400Ala	missense_variant	13/13	1		ENSP00000256452.3
IL5RA	ENST00000438560.5	c.1114A>C	p.Lys372Gln	missense_variant	11/11	2		ENSP00000390753.1
IL5RA	ENST00000418488.6	c.914A>C	p.Glu305Ala	missense_variant	11/11	5		ENSP00000388858.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Aug 21, 2024

The c.1199A>C (p.E400A) alteration is located in exon 1 (coding exon 1) of the IL5RA gene. This alteration results from a A to C substitution at nucleotide position 1199, causing the glutamic acid (E) at amino acid position 400 to be replaced by an alanine (A). 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	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;D;D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.74	T;.;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.33	T
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.10
Sift	Benign	0.050	D;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.88	P;P;P
Vest4		0.19
MutPred		0.30		.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.39
MPC		0.14
ClinPred		0.69	D
GERP RS		4.9
Varity_R		0.10
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs1702255464; hg19: chr3-3111973;