Genetic Variant IL13RA1:p.Ser295Pro (chrX-118766850-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001560.3(IL13RA1):c.883T>C(p.Ser295Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000957 in 1,044,676 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000043 ( 0 hom. 1 hem. )

Consequence

IL13RA1
NM_001560.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0890

Variant links:

Genes affected

IL13RA1 (HGNC:5974): (interleukin 13 receptor subunit alpha 1) The protein encoded by this gene is a subunit of the interleukin 13 receptor. This subunit forms a receptor complex with IL4 receptor alpha, a subunit shared by IL13 and IL4 receptors. This subunit serves as a primary IL13-binding subunit of the IL13 receptor, and may also be a component of IL4 receptors. This protein has been shown to bind tyrosine kinase TYK2, and thus may mediate the signaling processes that lead to the activation of JAK1, STAT3 and STAT6 induced by IL13 and IL4. [provided by RefSeq, Jul 2008]

IL13RA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18053481).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL13RA1	NM_001560.3 link	c.883T>C	p.Ser295Pro	missense_variant	Exon 8 of 11	ENST00000371666.8	NP_001551.1	P78552-1
IL13RA1	XM_047442096.1 link	c.883T>C	p.Ser295Pro	missense_variant	Exon 8 of 11		XP_047298052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL13RA1	ENST00000371666.8 link	c.883T>C	p.Ser295Pro	missense_variant	Exon 8 of 11	1	NM_001560.3	ENSP00000360730.3	P78552-1
IL13RA1	ENST00000652600.1 link	c.877T>C	p.Ser293Pro	missense_variant	Exon 9 of 12			ENSP00000498980.1	A0A494C1C4
IL13RA1	ENST00000481868.1 link	n.576T>C		non_coding_transcript_exon_variant	Exon 6 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

112251

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

34399

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000566

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000429

AC:

AN:

932425

Hom.:

Cov.:

AF XY:

0.00000374

AC XY:

AN XY:

267363

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000138

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000535

AC:

AN:

112251

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

34399

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000566

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.883T>C (p.S295P) alteration is located in exon 8 (coding exon 8) of the IL13RA1 gene. This alteration results from a T to C substitution at nucleotide position 883, causing the serine (S) at amino acid position 295 to be replaced by a proline (P). 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

0.28

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.8

DANN

Benign

0.86

DEOGEN2

Benign

0.30

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.58

M_CAP

Benign

0.051

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.23

Sift

Benign

0.21

Sift4G

Benign

0.29

Polyphen

0.63

Vest4

0.24

MutPred

0.57

Gain of catalytic residue at S295 (P = 0.0123);

MVP

0.56

MPC

0.27

ClinPred

0.059

GERP RS

1.4

Varity_R

0.70

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over