3-3070292-G-A

Position:

• chr3-3070292-G-A

Variant summary

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

The NM_175726.4(IL5RA):​c.1196C>T​(p.Thr399Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,611,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: IL5RA NM_175726.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

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=0.15218389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL5RA	NM_175726.4	c.1196C>T	p.Thr399Met	missense_variant	12/12	ENST00000446632.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL5RA	ENST00000446632.7	c.1196C>T	p.Thr399Met	missense_variant	12/12	5	NM_175726.4	P2
IL5RA	ENST00000256452.7	c.1196C>T	p.Thr399Met	missense_variant	13/13	1		P2
IL5RA	ENST00000438560.5	c.1111C>T	p.Arg371Trp	missense_variant	11/11	2		A2
IL5RA	ENST00000418488.6	c.911C>T	p.Thr304Met	missense_variant	11/11	5

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000805 AC: 20 AN: 248362 Hom.: 0 AF XY: 0.0000744 AC XY: 10 AN XY: 134446

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000720

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1459818 Hom.: 0 Cov.: 28 AF XY: 0.000128 AC XY: 93 AN XY: 726302

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74298

Gnomad4 AFR AF: 0.000579

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000111 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000273

EpiControl AF: 0.0000594

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

Dec 13, 2022

The c.1196C>T (p.T399M) alteration is located in exon 1 (coding exon 1) of the IL5RA gene. This alteration results from a C to T substitution at nucleotide position 1196, causing the threonine (T) at amino acid position 399 to be replaced by a methionine (M). 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	0.087
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.90	D;D;N;N;N
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.40
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0080	D
Vest4		0.13
MVP		0.77
ClinPred		0.41	T
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs146918848; hg19: chr3-3111976;