11-117989554-C-T

Position:

chr11-117989554-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001558.4(IL10RA):c.301C>T(p.Arg101Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

IL10RA
NM_001558.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.667

Variant links:

Genes affected

IL10RA (HGNC:5964): (interleukin 10 receptor subunit alpha) The protein encoded by this gene is a receptor for interleukin 10. This protein is structurally related to interferon receptors. It has been shown to mediate the immunosuppressive signal of interleukin 10, and thus inhibits the synthesis of proinflammatory cytokines. This receptor is reported to promote survival of progenitor myeloid cells through the insulin receptor substrate-2/PI 3-kinase/AKT pathway. Activation of this receptor leads to tyrosine phosphorylation of JAK1 and TYK2 kinases. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Jan 2009]

IL10RA links:

IL10RA (HGNC:):

IL10RA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 11-117989554-C-T is Pathogenic according to our data. Variant chr11-117989554-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL10RA	NM_001558.4 linkuse as main transcript	c.301C>T	p.Arg101Trp	missense_variant	3/7	ENST00000227752.8	NP_001549.2	Q13651
IL10RA	XM_047426882.1 linkuse as main transcript	c.241C>T	p.Arg81Trp	missense_variant	3/7		XP_047282838.1
IL10RA	XM_047426884.1 linkuse as main transcript	c.-81+1052C>T		intron_variant			XP_047282840.1
IL10RA	NR_026691.2 linkuse as main transcript	n.505C>T		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL10RA	ENST00000227752.8 linkuse as main transcript	c.301C>T	p.Arg101Trp	missense_variant	3/7	1	NM_001558.4	ENSP00000227752.4		Q13651

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251378

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inflammatory bowel disease 28

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Feb 28, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	Experimental studies have shown that this missense change affects IL10RA function (PMID: 22476154). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IL10RA protein function. ClinVar contains an entry for this variant (Variation ID: 39432). This missense change has been observed in individual(s) with autosomal recessive inflammatory bowel disease (PMID: 22476154, 22549091, 27699570, 28267044). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs368287711, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 101 of the IL10RA protein (p.Arg101Trp). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2012	- -

IL10RA-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2023

The IL10RA c.301C>T variant is predicted to result in the amino acid substitution p.Arg101Trp. This variant has been reported in the compound heterozygous and homozygous state in many individuals with very-early-onset inflammatory bowel disease (see, for example, Mao et al 2012. PubMed ID: 22476154; Huang et al 2017. PubMed ID: 28267044; Fang et al 2018. PubMed ID: 29531467). In vitro experimental studies suggest this variant impacts protein function (Mao et al 2012. PubMed ID: 22476154; Kotlarz et al 2012. PubMed ID: 22549091). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-117860269-C-T). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.1

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MutPred

0.83

Loss of methylation at R101 (P = 0.0116);

MVP

0.92

MPC

0.82

ClinPred

0.96

GERP RS

4.0

Varity_R

0.91

gMVP

0.80

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