NM_175726.4:c.385A>G

Variant names:

• chr3-3098273-T-C
• rs2290610
• NM_175726.4:c.385A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175726.4(IL5RA):​c.385A>G​(p.Ile129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,612,150 control chromosomes in the GnomAD database, including 112,267 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I129T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.37 (10557 hom., cov: 32)
  • Exomes 𝑓: 0.37 (101710 hom.)
• Consequence: IL5RA NM_175726.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.505
• Publications: 42 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.54885E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175726.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL5RA	NM_175726.4	MANE Select	c.385A>G	p.Ile129Val	missense	Exon 6 of 12	NP_783853.1
	IL5RA	NM_000564.5		c.385A>G	p.Ile129Val	missense	Exon 7 of 13	NP_000555.2
	IL5RA	NM_001243099.2		c.385A>G	p.Ile129Val	missense	Exon 6 of 11	NP_001230028.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL5RA	ENST00000446632.7	TSL:5 MANE Select	c.385A>G	p.Ile129Val	missense	Exon 6 of 12	ENSP00000412209.2
	IL5RA	ENST00000256452.7	TSL:1	c.385A>G	p.Ile129Val	missense	Exon 7 of 13	ENSP00000256452.3
	IL5RA	ENST00000311981.12	TSL:1	c.385A>G	p.Ile129Val	missense	Exon 7 of 11	ENSP00000309196.8

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55946 AN: 151920 Hom.: 10549 Cov.: 32

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.386

GnomAD2 exomes AF: 0.384 AC: 96516 AN: 251350 AF XY: 0.392

Gnomad AFR exome AF: 0.391

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.425

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.368 AC: 536899 AN: 1460112 Hom.: 101710 Cov.: 35 AF XY: 0.373 AC XY: 270857 AN XY: 726530

African (AFR) AF: 0.381 AC: 12726 AN: 33434

American (AMR) AF: 0.370 AC: 16560 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11951 AN: 26114

East Asian (EAS) AF: 0.356 AC: 14113 AN: 39694

South Asian (SAS) AF: 0.550 AC: 47409 AN: 86204

European-Finnish (FIN) AF: 0.229 AC: 12259 AN: 53420

Middle Eastern (MID) AF: 0.440 AC: 2537 AN: 5762

European-Non Finnish (NFE) AF: 0.357 AC: 396133 AN: 1110426

Other (OTH) AF: 0.385 AC: 23211 AN: 60346

GnomAD4 genome AF: 0.368 AC: 55985 AN: 152038 Hom.: 10557 Cov.: 32 AF XY: 0.367 AC XY: 27290 AN XY: 74316

African (AFR) AF: 0.384 AC: 15926 AN: 41460

American (AMR) AF: 0.372 AC: 5676 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1555 AN: 3470

East Asian (EAS) AF: 0.410 AC: 2119 AN: 5168

South Asian (SAS) AF: 0.555 AC: 2678 AN: 4822

European-Finnish (FIN) AF: 0.220 AC: 2328 AN: 10570

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24338 AN: 67954

Other (OTH) AF: 0.387 AC: 818 AN: 2112

Alfa AF: 0.368 Hom.: 34728

Bravo AF: 0.376

TwinsUK AF: 0.356 AC: 1320

ALSPAC AF: 0.365 AC: 1406

ESP6500AA AF: 0.392 AC: 1726

ESP6500EA AF: 0.367 AC: 3152

ExAC AF: 0.388 AC: 47142

Asia WGS AF: 0.493 AC: 1713 AN: 3478

EpiCase AF: 0.371

EpiControl AF: 0.371

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.0020
DANN	Benign	0.65
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.000015	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.51
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.036
MPC		0.029
ClinPred		0.0025	T
GERP RS		-4.2
Varity_R		0.038
gMVP		0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2290610; hg19: chr3-3139957; COSMIC: COSV56520778; COSMIC: COSV56520778;